The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Elyssa B Margolis - One of the best experts on this subject based on the ideXlab platform.
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differential modulation of Ventral Tegmental Area circuits by the nociceptin orphanin fq system
eNeuro, 2020Co-Authors: Joseph R Driscoll, Tanya L Wallace, Kasra A Mansourian, William J Martin, Elyssa B MargolisAbstract:The neuropeptide nociceptin/orphanin FQ (N/OFQ) can be released by stressors and is associated with disorders of emotion regulation and reward processing. N/OFQ and its receptor, NOP, are enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and Ventral Tegmental Area (VTA). We used whole cell electrophysiology in acute rat midbrain slices to investigate synaptic actions of N/OFQ. N/OFQ was primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+)) and non-dopaminergic (TH(-)) VTA neurons (effect at 1 μM: 20 ± 4 pA). Surprisingly, this effect was mediated by augmentation of postsynaptic GABAAR currents, unlike the substantia nigra pars compacta (SNc), where the N/OFQ induced outward currents were K+ channel dependent. A smaller population, 19% of all VTA neurons, responded to low concentrations N/OFQ with inward currents (10 nM: -11 ± 2 pA). Following 100 nM N/OFQ, the response to a second N/OFQ application was markedly diminished in VTA neurons (14 ± 10% of first response), but not in SNc neurons (90 ± 20% of first response). N/OFQ generated outward currents in medial prefrontal cortex (mPFC)-projecting VTA neurons, but inward currents in a subset of posterior anterior cingulate cortex-projecting VTA neurons. While N/OFQ inhibited NAc-projecting VTA cell bodies, it had little effect on electrically or optogenetically evoked terminal dopamine release in the NAc measured ex vivo with fast scan cyclic voltammetry. These results extend our understanding of the N/OFQ system in brainstem circuits implicated in many neurobehavioral disorders. Significance statement The neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are engaged under conditions of stress and are associated with reward processing disorders. Both peptide and receptor are highly enriched in Ventral Tegmental Area (VTA) pathways underlying motivation and reward. Using whole cell electrophysiology in rat midbrain slices we found: 1) NOPs are functional on both dopaminergic and non-dopaminergic VTA neurons; 2) N/OFQ differentially regulates VTA neurons based on neuroanatomical projection target; and 3) repeated application of N/OFQ produces evidence of receptor desensitization in VTA but not SNc neurons. These results reveal candidate mechanisms by which the NOP system regulates motivation and emotion.
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Ventral Tegmental Area cellular heterogeneity connectivity and behaviour
Nature Reviews Neuroscience, 2017Co-Authors: Marisela Morales, Elyssa B MargolisAbstract:Neurons in the Ventral Tegmental Area (VTA) are highly heterogeneous and project to a range of different brain regions. Morales and Margolis summarize recent efforts to characterise VTA neurons, dissect their circuitry and understand their roles in motivation- and reward-related behaviours. Dopamine-releasing neurons of the Ventral Tegmental Area (VTA) have central roles in reward-related and goal-directed behaviours. VTA dopamine-releasing neurons are heterogeneous in their afferent and efferent connectivity and, in some cases, release GABA or glutamate in addition to dopamine. Recent findings show that motivational signals arising from the VTA can also be carried by non-dopamine-releasing projection neurons, which have their own specific connectivity. Both dopamine-releasing and non-dopamine-releasing VTA neurons integrate afferent signals with local inhibitory or excitatory inputs to generate particular output firing patterns. Various individual inputs, outputs and local connections have been shown to be sufficient to generate reward- or aversion-related behaviour, indicative of the impressive contribution of this small population of neurons to behaviour.
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identification of rat Ventral Tegmental Area gabaergic neurons
PLOS ONE, 2012Co-Authors: Elyssa B Margolis, Marisela Morales, Patricia Himmels, Brian C Toy, Howard L FieldsAbstract:The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain Ventral Tegmental Area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23±3% of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABAB receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward.
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Identification of rat Ventral Tegmental Area GABAergic neurons
2012Co-Authors: Elyssa B Margolis, Marisela Morales, Brian Toy, Patricia Himmels, Howard L FieldsAbstract:The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain Ventral Tegmental Area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 2363 % of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABAB receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determin
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nucleus accumbens medium spiny neurons target non dopaminergic neurons in the Ventral Tegmental Area
The Journal of Neuroscience, 2011Co-Authors: Yanfang Xia, Elyssa B Margolis, Howard L Fields, Joseph R Driscoll, Linda Wilbrecht, Gregory O HjelmstadAbstract:The midbrain Ventral Tegmental Area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABAA or GABAB receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo . We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABAA receptors.
Marisela Morales - One of the best experts on this subject based on the ideXlab platform.
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Ventral Tegmental Area cellular heterogeneity connectivity and behaviour
Nature Reviews Neuroscience, 2017Co-Authors: Marisela Morales, Elyssa B MargolisAbstract:Neurons in the Ventral Tegmental Area (VTA) are highly heterogeneous and project to a range of different brain regions. Morales and Margolis summarize recent efforts to characterise VTA neurons, dissect their circuitry and understand their roles in motivation- and reward-related behaviours. Dopamine-releasing neurons of the Ventral Tegmental Area (VTA) have central roles in reward-related and goal-directed behaviours. VTA dopamine-releasing neurons are heterogeneous in their afferent and efferent connectivity and, in some cases, release GABA or glutamate in addition to dopamine. Recent findings show that motivational signals arising from the VTA can also be carried by non-dopamine-releasing projection neurons, which have their own specific connectivity. Both dopamine-releasing and non-dopamine-releasing VTA neurons integrate afferent signals with local inhibitory or excitatory inputs to generate particular output firing patterns. Various individual inputs, outputs and local connections have been shown to be sufficient to generate reward- or aversion-related behaviour, indicative of the impressive contribution of this small population of neurons to behaviour.
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a glutamatergic reward input from the dorsal raphe to Ventral Tegmental Area dopamine neurons
Nature Communications, 2014Co-Authors: Shiliang Zhang, Carl R Lupica, Huiling Wang, Huikun Wang, Jose De Jesus Aceves Buendia, Alexander F Hoffman, Rebecca P Seal, Marisela MoralesAbstract:Electrical stimulation of the dorsal raphe (DR) and Ventral Tegmental Area (VTA) activates the fibres of the same reward pathway but the phenotype of this pathway and the direction of the reward-relevant fibres have not been determined. Here we report rewarding effects following activation of a DR-originating pathway consisting of vesicular glutamate transporter 3 (VGluT3) containing neurons that form asymmetric synapses onto VTA dopamine neurons that project to nucleus accumbens. Optogenetic VTA activation of this projection elicits AMPA-mediated synaptic excitatory currents in VTA mesoaccumbens dopaminergic neurons and causes dopamine release in nucleus accumbens. Activation also reinforces instrumental behaviour and establishes conditioned place preferences. These findings indicate that the DR-VGluT3 pathway to VTA utilizes glutamate as a neurotransmitter and is a substrate linking the DR-one of the most sensitive reward sites in the brain--to VTA dopaminergic neurons.
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identification of rat Ventral Tegmental Area gabaergic neurons
PLOS ONE, 2012Co-Authors: Elyssa B Margolis, Marisela Morales, Patricia Himmels, Brian C Toy, Howard L FieldsAbstract:The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain Ventral Tegmental Area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23±3% of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABAB receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward.
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Identification of rat Ventral Tegmental Area GABAergic neurons
2012Co-Authors: Elyssa B Margolis, Marisela Morales, Brian Toy, Patricia Himmels, Howard L FieldsAbstract:The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain Ventral Tegmental Area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 2363 % of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABAB receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determin
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glutamatergic neurons are present in the rat Ventral Tegmental Area
European Journal of Neuroscience, 2007Co-Authors: Tsuyoshi Yamaguchi, Whitney Sheen, Marisela MoralesAbstract:The Ventral Tegmental Area (VTA) is thought to play an important role in reward function. Two populations of neurons, containing either dopamine (DA) or γ-amino butyric acid (GABA), have been extensively characterized in this Area. However, recent electrophysiological studies are consistent with the notion that neurons that utilize neurotransmitters other than DA or GABA are likely to be present in the VTA. Given the pronounced phenotypic diversity of neurons in this region, we have proposed that additional cell types, such as those that express the neurotransmitter glutamate may also be present in this Area. Thus, by using in situ hybridization histochemistry we investigated whether transcripts encoded by genes for the two vesicular glutamate transporters, VGluT1 or VGluT2, were expressed in the VTA. We found that VGluT2 mRNA but not VGluT1 mRNA is expressed in the VTA. Neurons expressing VGluT2 mRNA were differentially distributed throughout the rostro-caudal and medio-lateral aspects of the VTA, with the highest concentration detected in rostro-medial Areas. Phenotypic characterization with double in situ hybridization of these neurons indicated that they rarely co–expressed mRNAs for tyrosine hydroxylase (TH, marker for DAergic neurons) or glutamic acid decarboxylase (GAD, marker for GABAergic neurons). Based on the results described here, we concluded that the VTA contains glutamatergic neurons that in their vast majority are clearly non-DAergic and non-GABAergic.
Howard L Fields - One of the best experts on this subject based on the ideXlab platform.
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Ventral Tegmental Area glutamate neurons electrophysiological properties and projections
The Journal of Neuroscience, 2012Co-Authors: Thomas S Hnasko, Gregory O Hjelmstad, Howard L Fields, Robert H EdwardsAbstract:The Ventral Tegmental Area (VTA) has a central role in the neural processes that underlie motivation and behavioral reinforcement. Although thought to contain only dopamine and GABA neurons, the VTA also includes a recently discovered population of glutamate neurons identified through the expression of the vesicular glutamate transporter VGLUT2. A subset of VGLUT2+ VTA neurons corelease dopamine with glutamate at terminals in the NAc, but others do not express dopaminergic markers and remain poorly characterized. Using transgenic mice that express fluorescent proteins in distinct cell populations, we now find that both dopamine and glutamate neurons in the medial VTA exhibit a smaller hyperpolarization-activated current (Ih) than more lateral dopamine neurons and less consistent inhibition by dopamine D2 receptor agonists. In addition, VGLUT2+ VTA neurons project to the nucleus accumbens (NAc), lateral habenula, Ventral pallidum (VP), and amygdala. Optical stimulation of VGLUT2+ projections expressing channelrhodopsin-2 further reveals functional excitatory synapses in the VP as well as the NAc. Thus, glutamate neurons form a physiologically and anatomically distinct subpopulation of VTA projection neurons.
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identification of rat Ventral Tegmental Area gabaergic neurons
PLOS ONE, 2012Co-Authors: Elyssa B Margolis, Marisela Morales, Patricia Himmels, Brian C Toy, Howard L FieldsAbstract:The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain Ventral Tegmental Area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23±3% of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABAB receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward.
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Identification of rat Ventral Tegmental Area GABAergic neurons
2012Co-Authors: Elyssa B Margolis, Marisela Morales, Brian Toy, Patricia Himmels, Howard L FieldsAbstract:The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain Ventral Tegmental Area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 2363 % of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABAB receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determin
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nucleus accumbens medium spiny neurons target non dopaminergic neurons in the Ventral Tegmental Area
The Journal of Neuroscience, 2011Co-Authors: Yanfang Xia, Elyssa B Margolis, Howard L Fields, Joseph R Driscoll, Linda Wilbrecht, Gregory O HjelmstadAbstract:The midbrain Ventral Tegmental Area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABAA or GABAB receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo . We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABAA receptors.
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Ventral Tegmental Area neurons in learned appetitive behavior and positive reinforcement
Annual Review of Neuroscience, 2007Co-Authors: Howard L Fields, Elyssa B Margolis, Gregory O Hjelmstad, Saleem M NicolaAbstract:Ventral Tegmental Area (VTA) neuron firing precedes behaviors elicited by reward-predictive sensory cues and scales with the magnitude and unpredictability of received rewards. These patterns are consistent with roles in the performance of learned appetitive behaviors and in positive reinforcement, respectively. The VTA includes subpopulations of neurons with different afferent connections, neurotransmitter content, and projection targets. Because the VTA and substantia nigra pars compacta are the sole sources of striatal and limbic forebrain dopamine, measurements of dopamine release and manipulations of dopamine function have provided critical evidence supporting a VTA contribution to these functions. However, the VTA also sends GABAergic and glutamatergic projections to the nucleus accumbens and prefrontal cortex. Furthermore, VTA-mediated but dopamine-independent positive reinforcement has been demonstrated. Consequently, identifying the neurotransmitter content and projection target of VTA neurons recorded in vivo will be critical for determining their contribution to learned appetitive behaviors.
Christian Luscher - One of the best experts on this subject based on the ideXlab platform.
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cocaine disinhibits dopamine neurons by potentiation of gaba transmission in the Ventral Tegmental Area
Science, 2013Co-Authors: Christina Bocklisch, Jovi C Y Wong, Christian Luscher, Vincent Pascoli, David R C House, Cedric Yvon, Mathias De Roo, Kelly R TanAbstract:Drug-evoked synaptic plasticity in the mesolimbic system reshapes circuit function and drives drug-adaptive behavior. Much research has focused on excitatory transmission in the Ventral Tegmental Area (VTA) and the nucleus accumbens (NAc). How drug-evoked synaptic plasticity of inhibitory transmission affects circuit adaptations remains unknown. We found that medium spiny neurons expressing dopamine (DA) receptor type 1 (D1R-MSNs) of the NAc project to the VTA, strongly preferring the GABA neurons of the VTA. Repeated in vivo exposure to cocaine evoked synaptic potentiation at this synapse, occluding homosynaptic inhibitory long-term potentiation. The activity of the VTA GABA neurons was thus reduced and DA neurons were disinhibited. Cocaine-evoked potentiation of GABA release from D1R-MSNs affected drug-adaptive behavior, which identifies these neurons as a promising target for novel addiction treatments.
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cocaine inverts rules for synaptic plasticity of glutamate transmission in the Ventral Tegmental Area
Nature Neuroscience, 2011Co-Authors: Manuel Mameli, Christian Luscher, Camilla Bellone, Matthew BrownAbstract:The manner in which drug-evoked synaptic plasticity affects reward circuits remains largely elusive. We found that cocaine reduced NMDA receptor excitatory postsynaptic currents and inserted GluA2-lacking AMPA receptors in dopamine neurons of mice. Consequently, a stimulation protocol pairing glutamate release with hyperpolarizing current injections further strengthened synapses after cocaine treatment. Our data suggest that early cocaine-evoked plasticity in the Ventral Tegmental Area inverts the rules for activity-dependent plasticity, eventually leading to addictive behavior.
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rapid synthesis and synaptic insertion of glur2 for mglur ltd in the Ventral Tegmental Area
Science, 2007Co-Authors: Manuel Mameli, Benedicte Balland, Rafael Lujan, Christian LuscherAbstract:The activation of metabotropic glutamate receptors (mGluRs) leads to long-term depression (mGluR-LTD) at many synapses of the brain. The induction of mGluR-LTD is well characterized, whereas the mechanisms underlying its expression remain largely elusive. mGluR-LTD in the Ventral Tegmental Area (VTA) efficiently reverses cocaine-induced strengthening of excitatory inputs onto dopamine neurons. We show that mGluR-LTD is expressed by an exchange of GluR2-lacking AMPA receptors for GluR2-containing receptors with a lower single-channel conductance. The synaptic insertion of GluR2 depends on de novo protein synthesis via rapid messenger RNA translation of GluR2. Regulated synthesis of GluR2 in the VTA is therefore required to reverse cocaine-induced synaptic plasticity.
Mark A Ungless - One of the best experts on this subject based on the ideXlab platform.
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stereological estimates of dopaminergic gabaergic and glutamatergic neurons in the Ventral Tegmental Area substantia nigra and retrorubral field in the rat
Neuroscience, 2008Co-Authors: Radha Goh Nairroberts, S D Chatelainbadie, Elizabeth Benson, Helen Whitecooper, J P Bolam, Mark A UnglessAbstract:Midbrain dopamine neurons in the Ventral Tegmental Area, substantia nigra and retrorubral field play key roles in reward processing, learning and memory, and movement. Within these midbrain regions and admixed with the dopamine neurons, are also substantial populations of GABAergic neurons that regulate dopamine neuron activity and have projection targets similar to those of dopamine neurons. Additionally, there is a small group of putative glutamatergic neurons within the Ventral Tegmental Area whose function remains unclear. Although dopamine neurons have been intensively studied and quantified, there is little quantitative information regarding the GABAergic and glutamatergic neurons. We therefore used unbiased stereological methods to estimate the number of dopaminergic, GABAergic and glutamatergic cells in these regions in the rat. Neurons were identified using a combination of immunohistochemistry (tyrosine hydroxylase) and in situ hybridization (glutamic acid decarboxylase mRNA and vesicular glutamate transporter 2 mRNA). In substantia nigra pars compacta 29% of cells were glutamic acid decarboxylase mRNA-positive, 58% in the retrorubral field and 35% in the Ventral Tegmental Area. There were further differences in the relative sizes of the GABAergic populations in subnuclei of the Ventral Tegmental Area. Thus, glutamic acid decarboxylase mRNA-positive neurons represented 12% of cells in the interfascicular nucleus, 30% in the parabrachial nucleus, and 45% in the parainterfascicular nucleus. Vesicular glutamate transporter 2 mRNA-positive neurons were present in the Ventral Tegmental Area, but not substantia nigra or retrorubral field. They were mainly confined to the rostro-medial region of the Ventral Tegmental Area, and represented approximately 2–3% of the total neurons counted (∼1600 cells). These results demonstrate that GABAergic and glutamatergic neurons represent large proportions of the neurons in what are traditionally considered as dopamine nuclei and that there are considerable heterogeneities in the proportions of cell types in the different dopaminergic midbrain regions.
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uniform inhibition of dopamine neurons in the Ventral Tegmental Area by aversive stimuli
Science, 2004Co-Authors: Mark A Ungless, Peter J Magill, Paul J BolamAbstract:Dopamine neurons play a key role in reward-related behaviors. Reward coding theories predict that dopamine neurons will be inhibited by or will not respond to aversive stimuli. Paradoxically, between 3 and 49% of presumed dopamine neurons are excited by aversive stimuli. We found that, in the Ventral Tegmental Area of anesthetized rats, the population of presumed dopamine neurons that are excited by aversive stimuli is actually not dopaminergic. The identified dopamine neurons were inhibited by the aversive stimulus. These findings suggest that dopamine neurons are specifically excited by reward and that a population of nondopamine neurons is excited by aversive stimuli.
