Publications from the Neuronal Networks Section.
2016
Root, David H; Wang, Hui-Ling; Liu, Bing; Barker, David J; Mod, Laszlo; Szocsics, Peter; Silva, Afonso C; Magloczky, Zsofia; Morales, Marisela
Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans. Journal Article
In: Sci Rep, vol. 6, pp. 30615, 2016, ISSN: 2045-2322 (Electronic); 2045-2322 (Linking).
@article{Root2016,
title = {Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans.},
author = {David H Root and Hui-Ling Wang and Bing Liu and David J Barker and Laszlo Mod and Peter Szocsics and Afonso C Silva and Zsofia Magloczky and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27477243},
doi = {10.1038/srep30615},
issn = {2045-2322 (Electronic); 2045-2322 (Linking)},
year = {2016},
date = {2016-08-01},
journal = {Sci Rep},
volume = {6},
pages = {30615},
address = {Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, 251 Bayview Blvd Suite 200, Baltimore, MD 21224, USA.},
abstract = {The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson's disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson's disease.
Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Barker, David J; Miranda-Barrientos, Jorge; Morales, Marisela
VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons. Journal Article
In: Nat Neurosci, vol. 19, no. 5, pp. 725–733, 2016, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
@article{Qi2016,
title = {VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons.},
author = {Jia Qi and Shiliang Zhang and Hui-Ling Wang and David J Barker and Jorge Miranda-Barrientos and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27019014},
doi = {10.1038/nn.4281},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2016},
date = {2016-05-01},
journal = {Nat Neurosci},
volume = {19},
number = {5},
pages = {725--733},
address = {Neuronal Networks Section, Integrative Neuroscience Research Branch, US National Institute on Drug Abuse, Baltimore, Maryland, USA.},
abstract = {The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens glutamatergic pathway remains unknown. Here we report that nAcc photoactivation of mesoaccumbens glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens glutamatergic fibers lack GABA, the aversion evoked by their photoactivation depended on glutamate- and GABA-receptor signaling, and not on dopamine-receptor signaling. We found that mesoaccumbens glutamatergic fibers established multiple asymmetric synapses on single parvalbumin GABAergic interneurons and that nAcc photoactivation of these fibers drove AMPA-mediated cellular firing of parvalbumin GABAergic interneurons. These parvalbumin GABAergic interneurons in turn inhibited nAcc medium spiny output neurons, thereby controlling inhibitory neurotransmission in nAcc. To our knowledge, the mesoaccumbens glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin GABAergic interneurons.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens glutamatergic pathway remains unknown. Here we report that nAcc photoactivation of mesoaccumbens glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens glutamatergic fibers lack GABA, the aversion evoked by their photoactivation depended on glutamate- and GABA-receptor signaling, and not on dopamine-receptor signaling. We found that mesoaccumbens glutamatergic fibers established multiple asymmetric synapses on single parvalbumin GABAergic interneurons and that nAcc photoactivation of these fibers drove AMPA-mediated cellular firing of parvalbumin GABAergic interneurons. These parvalbumin GABAergic interneurons in turn inhibited nAcc medium spiny output neurons, thereby controlling inhibitory neurotransmission in nAcc. To our knowledge, the mesoaccumbens glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin GABAergic interneurons.
2015
Wang, Hui-Ling; Qi, Jia; Zhang, Shiliang; Wang, Huikun; Morales, Marisela
Rewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons. Journal Article
In: J Neurosci, vol. 35, no. 48, pp. 15948–15954, 2015, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Wang2015,
title = {Rewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons.},
author = {Hui-Ling Wang and Jia Qi and Shiliang Zhang and Huikun Wang and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26631475},
doi = {10.1523/JNEUROSCI.3428-15.2015},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2015},
date = {2015-12-02},
journal = {J Neurosci},
volume = {35},
number = {48},
pages = {15948--15954},
address = {Neuronal Networks Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.},
abstract = {Ventral tegmental area (VTA) neurons play roles in reward and aversion. The VTA has three major neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. VTA glutamatergic neurons--expressing vesicular glutamate transporter-2 (VGluT2)--project to limbic and cortical regions, but also excite neighboring dopaminergic neurons. Here, we test whether local photoactivation of VTA VGluT2 neurons expressing Channelrhodopsin-2 (ChR2) under the VGluT2 promoter causes place preference and supports operant responding for the stimulation. By using a Cre-dependent viral vector, ChR2 (tethered to mCherry) was expressed in VTA glutamatergic neurons of VGluT2::Cre mice. The mCherry distribution was evaluated by immunolabeling. By confocal microscopy, we detected expression of mCherry in VTA cell bodies and local processes. In contrast, VGluT2 expression was restricted to varicosities, some of them coexpressing mCherry. By electron microscopy, we determined that mCherry-VGluT2 varicosities correspond to axon terminals, forming asymmetric synapses on neighboring dopaminergic neurons. These findings indicate that ChR2 was present in terminals containing glutamatergic synaptic vesicles and involved in local synaptic connections. Photoactivation of VTA slices from ChR2-expressing mice induced AMPA/NMDA receptor-dependent firing of dopaminergic neurons projecting to the nucleus accumbens. VTA photoactivation of ChR2-expressing mice reinforced instrumental behavior and established place preferences. VTA injections of AMPA or NMDA receptor antagonists blocked optical self-stimulation and place preference. These findings suggest a role in reward function for VTA glutamatergic neurons through local excitatory synapses on mesoaccumbens dopaminergic neurons.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Ventral tegmental area (VTA) neurons play roles in reward and aversion. The VTA has three major neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. VTA glutamatergic neurons--expressing vesicular glutamate transporter-2 (VGluT2)--project to limbic and cortical regions, but also excite neighboring dopaminergic neurons. Here, we test whether local photoactivation of VTA VGluT2 neurons expressing Channelrhodopsin-2 (ChR2) under the VGluT2 promoter causes place preference and supports operant responding for the stimulation. By using a Cre-dependent viral vector, ChR2 (tethered to mCherry) was expressed in VTA glutamatergic neurons of VGluT2::Cre mice. The mCherry distribution was evaluated by immunolabeling. By confocal microscopy, we detected expression of mCherry in VTA cell bodies and local processes. In contrast, VGluT2 expression was restricted to varicosities, some of them coexpressing mCherry. By electron microscopy, we determined that mCherry-VGluT2 varicosities correspond to axon terminals, forming asymmetric synapses on neighboring dopaminergic neurons. These findings indicate that ChR2 was present in terminals containing glutamatergic synaptic vesicles and involved in local synaptic connections. Photoactivation of VTA slices from ChR2-expressing mice induced AMPA/NMDA receptor-dependent firing of dopaminergic neurons projecting to the nucleus accumbens. VTA photoactivation of ChR2-expressing mice reinforced instrumental behavior and established place preferences. VTA injections of AMPA or NMDA receptor antagonists blocked optical self-stimulation and place preference. These findings suggest a role in reward function for VTA glutamatergic neurons through local excitatory synapses on mesoaccumbens dopaminergic neurons.
Zhang, Shiliang; Qi, Jia; Li, Xueping; Wang, Hui-Ling; Britt, Jonathan P; Hoffman, Alexander F; Bonci, Antonello; Lupica, Carl R; Morales, Marisela
Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons. Journal Article
In: Nat Neurosci, vol. 18, no. 3, pp. 386–392, 2015, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
@article{Zhang2015,
title = {Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons.},
author = {Shiliang Zhang and Jia Qi and Xueping Li and Hui-Ling Wang and Jonathan P Britt and Alexander F Hoffman and Antonello Bonci and Carl R Lupica and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25664911},
doi = {10.1038/nn.3945},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2015},
date = {2015-03-01},
journal = {Nat Neurosci},
volume = {18},
number = {3},
pages = {386--392},
address = {National Institute on Drug Abuse, Neuronal Networks Section, US National Institutes of Health, Baltimore, Maryland, USA.},
abstract = {Mesoaccumbens fibers are thought to co-release dopamine and glutamate. However, the mechanism is unclear, and co-release by mesoaccumbens fibers has not been documented. Using electron microcopy, we found that some mesoaccumbens fibers have vesicular transporters for dopamine (VMAT2) in axon segments that are continuous with axon terminals that lack VMAT2, but contain vesicular glutamate transporters type 2 (VGluT2). In vivo overexpression of VMAT2 did not change the segregation of the two vesicular types, suggesting the existence of highly regulated mechanisms for maintaining this segregation. The mesoaccumbens axon terminals containing VGluT2 vesicles make asymmetric synapses, commonly associated with excitatory signaling. Using optogenetics, we found that dopamine and glutamate were released from the same mesoaccumbens fibers. These findings reveal a complex type of signaling by mesoaccumbens fibers in which dopamine and glutamate can be released from the same axons, but are not normally released at the same site or from the same synaptic vesicles.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mesoaccumbens fibers are thought to co-release dopamine and glutamate. However, the mechanism is unclear, and co-release by mesoaccumbens fibers has not been documented. Using electron microcopy, we found that some mesoaccumbens fibers have vesicular transporters for dopamine (VMAT2) in axon segments that are continuous with axon terminals that lack VMAT2, but contain vesicular glutamate transporters type 2 (VGluT2). In vivo overexpression of VMAT2 did not change the segregation of the two vesicular types, suggesting the existence of highly regulated mechanisms for maintaining this segregation. The mesoaccumbens axon terminals containing VGluT2 vesicles make asymmetric synapses, commonly associated with excitatory signaling. Using optogenetics, we found that dopamine and glutamate were released from the same mesoaccumbens fibers. These findings reveal a complex type of signaling by mesoaccumbens fibers in which dopamine and glutamate can be released from the same axons, but are not normally released at the same site or from the same synaptic vesicles.
Root, David H; Hoffman, Alexander F; Good, Cameron H; Zhang, Shiliang; Gigante, Eduardo; Lupica, Carl R; Morales, Marisela
Norepinephrine activates dopamine D4 receptors in the rat lateral habenula. Journal Article
In: J Neurosci, vol. 35, no. 8, pp. 3460–3469, 2015, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Root2015,
title = {Norepinephrine activates dopamine D4 receptors in the rat lateral habenula.},
author = {David H Root and Alexander F Hoffman and Cameron H Good and Shiliang Zhang and Eduardo Gigante and Carl R Lupica and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25716845},
doi = {10.1523/JNEUROSCI.4525-13.2015},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2015},
date = {2015-02-25},
journal = {J Neurosci},
volume = {35},
number = {8},
pages = {3460--3469},
address = {Neuronal Networks Section, Integrative Neuroscience Research Branch and.},
abstract = {The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function.
2014
Morales, M; Root, D H
Glutamate neurons within the midbrain dopamine regions. Journal Article
In: Neuroscience, vol. 282, pp. 60–68, 2014, ISSN: 1873-7544 (Electronic); 0306-4522 (Linking).
@article{Morales2014,
title = {Glutamate neurons within the midbrain dopamine regions.},
author = {M Morales and D H Root},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24875175},
doi = {10.1016/j.neuroscience.2014.05.032},
issn = {1873-7544 (Electronic); 0306-4522 (Linking)},
year = {2014},
date = {2014-12-12},
journal = {Neuroscience},
volume = {282},
pages = {60--68},
address = {Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, 251 Bayview Boulevard, Suite 200, Baltimore, MD 21224, United States. Electronic address: mmorales@intra.nida.nih.gov.},
abstract = {Midbrain dopamine systems play important roles in Parkinson's disease, schizophrenia, addiction, and depression. The participation of midbrain dopamine systems in diverse clinical contexts suggests these systems are highly complex. Midbrain dopamine regions contain at least three neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. Here, we review the locations, subtypes, and functions of glutamatergic neurons within midbrain dopamine regions. Vesicular glutamate transporter 2 (VGluT2) mRNA-expressing neurons are observed within each midbrain dopamine system. Within rat retrorubral field (RRF), large populations of VGluT2 neurons are observed throughout its anteroposterior extent. Within rat substantia nigra pars compacta (SNC), VGluT2 neurons are observed centrally and caudally, and are most dense within the laterodorsal subdivision. RRF and SNC rat VGluT2 neurons lack tyrosine hydroxylase (TH), making them an entirely distinct population of neurons from dopaminergic neurons. The rat ventral tegmental area (VTA) contains the most heterogeneous populations of VGluT2 neurons. VGluT2 neurons are found in each VTA subnucleus but are most dense within the anterior midline subnuclei. Some subpopulations of rat VGluT2 neurons co-express TH or glutamic acid decarboxylase (GAD), but most of the VGluT2 neurons lack TH or GAD. Different subsets of rat VGluT2-TH neurons exist based on the presence or absence of vesicular monoamine transporter 2, dopamine transporter, or D2 dopamine receptor. Thus, the capacity by which VGluT2-TH neurons may release dopamine will differ based on their capacity to accumulate vesicular dopamine, uptake extracellular dopamine, or be autoregulated by dopamine. Rat VTA VGluT2 neurons exhibit intrinsic VTA projections and extrinsic projections to the accumbens and to the prefrontal cortex. Mouse VTA VGluT2 neurons project to accumbens shell, prefrontal cortex, ventral pallidum, amygdala, and lateral habenula. Given their molecular diversity and participation in circuits involved in addiction, we hypothesize that individual VGluT2 subpopulations of neurons play unique roles in addiction and other disorders.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Midbrain dopamine systems play important roles in Parkinson's disease, schizophrenia, addiction, and depression. The participation of midbrain dopamine systems in diverse clinical contexts suggests these systems are highly complex. Midbrain dopamine regions contain at least three neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. Here, we review the locations, subtypes, and functions of glutamatergic neurons within midbrain dopamine regions. Vesicular glutamate transporter 2 (VGluT2) mRNA-expressing neurons are observed within each midbrain dopamine system. Within rat retrorubral field (RRF), large populations of VGluT2 neurons are observed throughout its anteroposterior extent. Within rat substantia nigra pars compacta (SNC), VGluT2 neurons are observed centrally and caudally, and are most dense within the laterodorsal subdivision. RRF and SNC rat VGluT2 neurons lack tyrosine hydroxylase (TH), making them an entirely distinct population of neurons from dopaminergic neurons. The rat ventral tegmental area (VTA) contains the most heterogeneous populations of VGluT2 neurons. VGluT2 neurons are found in each VTA subnucleus but are most dense within the anterior midline subnuclei. Some subpopulations of rat VGluT2 neurons co-express TH or glutamic acid decarboxylase (GAD), but most of the VGluT2 neurons lack TH or GAD. Different subsets of rat VGluT2-TH neurons exist based on the presence or absence of vesicular monoamine transporter 2, dopamine transporter, or D2 dopamine receptor. Thus, the capacity by which VGluT2-TH neurons may release dopamine will differ based on their capacity to accumulate vesicular dopamine, uptake extracellular dopamine, or be autoregulated by dopamine. Rat VTA VGluT2 neurons exhibit intrinsic VTA projections and extrinsic projections to the accumbens and to the prefrontal cortex. Mouse VTA VGluT2 neurons project to accumbens shell, prefrontal cortex, ventral pallidum, amygdala, and lateral habenula. Given their molecular diversity and participation in circuits involved in addiction, we hypothesize that individual VGluT2 subpopulations of neurons play unique roles in addiction and other disorders.
Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Wang, Huikun; de Jesus Aceves Buendia, Jose; Hoffman, Alexander F; Lupica, Carl R; Seal, Rebecca P; Morales, Marisela
A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons. Journal Article
In: Nat Commun, vol. 5, pp. 5390, 2014, ISSN: 2041-1723 (Electronic); 2041-1723 (Linking).
@article{Qi2014,
title = {A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.},
author = {Jia Qi and Shiliang Zhang and Hui-Ling Wang and Huikun Wang and Jose de Jesus Aceves Buendia and Alexander F Hoffman and Carl R Lupica and Rebecca P Seal and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25388237},
doi = {10.1038/ncomms6390},
issn = {2041-1723 (Electronic); 2041-1723 (Linking)},
year = {2014},
date = {2014-11-12},
journal = {Nat Commun},
volume = {5},
pages = {5390},
address = {National Institute on Drug Abuse, Neuronal Networks Section, National Institutes of Health, Baltimore, Maryland, USA.},
abstract = {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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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.
Root, David H; Mejias-Aponte, Carlos A; Zhang, Shiliang; Wang, Hui-Ling; Hoffman, Alexander F; Lupica, Carl R; Morales, Marisela
Single rodent mesohabenular axons release glutamate and GABA. Journal Article
In: Nat Neurosci, vol. 17, no. 11, pp. 1543–1551, 2014, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
@article{Root2014,
title = {Single rodent mesohabenular axons release glutamate and GABA.},
author = {David H Root and Carlos A Mejias-Aponte and Shiliang Zhang and Hui-Ling Wang and Alexander F Hoffman and Carl R Lupica and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25242304},
doi = {10.1038/nn.3823},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2014},
date = {2014-11-01},
journal = {Nat Neurosci},
volume = {17},
number = {11},
pages = {1543--1551},
address = {Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.},
abstract = {The lateral habenula (LHb) is involved in reward, aversion, addiction and depression through descending interactions with several brain structures, including the ventral tegmental area (VTA). The VTA provides reciprocal inputs to LHb, but their actions are unclear. Here we show that the majority of rat and mouse VTA neurons innervating LHb coexpress markers for both glutamate signaling (vesicular glutamate transporter 2; VGluT2) and GABA signaling (glutamic acid decarboxylase; GAD, and vesicular GABA transporter; VGaT). A single axon from these mesohabenular neurons coexpresses VGluT2 protein and VGaT protein and, surprisingly, establishes symmetric and asymmetric synapses on LHb neurons. In LHb slices, light activation of mesohabenular fibers expressing channelrhodopsin2 driven by VGluT2 (Slc17a6) or VGaT (Slc32a1) promoters elicits release of both glutamate and GABA onto single LHb neurons. In vivo light activation of mesohabenular terminals inhibits or excites LHb neurons. Our findings reveal an unanticipated type of VTA neuron that cotransmits glutamate and GABA and provides the majority of mesohabenular inputs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The lateral habenula (LHb) is involved in reward, aversion, addiction and depression through descending interactions with several brain structures, including the ventral tegmental area (VTA). The VTA provides reciprocal inputs to LHb, but their actions are unclear. Here we show that the majority of rat and mouse VTA neurons innervating LHb coexpress markers for both glutamate signaling (vesicular glutamate transporter 2; VGluT2) and GABA signaling (glutamic acid decarboxylase; GAD, and vesicular GABA transporter; VGaT). A single axon from these mesohabenular neurons coexpresses VGluT2 protein and VGaT protein and, surprisingly, establishes symmetric and asymmetric synapses on LHb neurons. In LHb slices, light activation of mesohabenular fibers expressing channelrhodopsin2 driven by VGluT2 (Slc17a6) or VGaT (Slc32a1) promoters elicits release of both glutamate and GABA onto single LHb neurons. In vivo light activation of mesohabenular terminals inhibits or excites LHb neurons. Our findings reveal an unanticipated type of VTA neuron that cotransmits glutamate and GABA and provides the majority of mesohabenular inputs.
Root, David H; Mejias-Aponte, Carlos A; Qi, Jia; Morales, Marisela
Role of glutamatergic projections from ventral tegmental area to lateral habenula in aversive conditioning. Journal Article
In: J Neurosci, vol. 34, no. 42, pp. 13906–13910, 2014, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Root2014,
title = {Role of glutamatergic projections from ventral tegmental area to lateral habenula in aversive conditioning.},
author = {David H Root and Carlos A Mejias-Aponte and Jia Qi and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25319687},
doi = {10.1523/JNEUROSCI.2029-14.2014},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2014},
date = {2014-10-15},
journal = {J Neurosci},
volume = {34},
number = {42},
pages = {13906--13910},
address = {Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland 21224.},
abstract = {The ventral tegmental area (VTA) plays roles in both reward and aversion. The participation of VTA in diverse behaviors likely reflects its heterogeneous neuronal phenotypes and circuits. Recent findings indicate that VTA GABAergic neurons that coexpress tyrosine hydroxylase (TH) projecting to lateral habenula (LHb) play a role in reward. In addition to these mesohabenular TH-GABAergic neurons, the VTA has many neurons expressing vesicular glutamate transporter 2 (VGluT2) that also project to LHb. To determine the behavioral role of mesohabenular VGluT2 neurons, we targeted channelrhodopsin2 to VTA VGluT2 neurons of VGluT2::Cre mice. These mice were tested in an apparatus where moving into one chamber stimulated VTA VGluT2 projections within the LHb, and exiting the chamber inactivated the stimulation. We found that mice spent significantly less time in the chamber where VGluT2 mesohabenular fiber stimulation occurred. Mice that received injections of mixed AMPA and NMDA glutamate receptor antagonists in LHb were unresponsive to VGluT2-mesohabenular fiber stimulation, demonstrating the participation of LHb glutamate receptors in mesohabenular stimulation-elicited aversion. In the absence of light stimulation, mice showed a conditioned place aversion to the chamber that was previously associated with VGluT2-mesohabenular fiber stimulation. We conclude that there is a glutamatergic signal from VTA VGluT2-mesohabenular neurons that plays a role in aversion by activating LHb glutamatergic receptors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The ventral tegmental area (VTA) plays roles in both reward and aversion. The participation of VTA in diverse behaviors likely reflects its heterogeneous neuronal phenotypes and circuits. Recent findings indicate that VTA GABAergic neurons that coexpress tyrosine hydroxylase (TH) projecting to lateral habenula (LHb) play a role in reward. In addition to these mesohabenular TH-GABAergic neurons, the VTA has many neurons expressing vesicular glutamate transporter 2 (VGluT2) that also project to LHb. To determine the behavioral role of mesohabenular VGluT2 neurons, we targeted channelrhodopsin2 to VTA VGluT2 neurons of VGluT2::Cre mice. These mice were tested in an apparatus where moving into one chamber stimulated VTA VGluT2 projections within the LHb, and exiting the chamber inactivated the stimulation. We found that mice spent significantly less time in the chamber where VGluT2 mesohabenular fiber stimulation occurred. Mice that received injections of mixed AMPA and NMDA glutamate receptor antagonists in LHb were unresponsive to VGluT2-mesohabenular fiber stimulation, demonstrating the participation of LHb glutamate receptors in mesohabenular stimulation-elicited aversion. In the absence of light stimulation, mice showed a conditioned place aversion to the chamber that was previously associated with VGluT2-mesohabenular fiber stimulation. We conclude that there is a glutamatergic signal from VTA VGluT2-mesohabenular neurons that plays a role in aversion by activating LHb glutamatergic receptors.
2013
Li, Xueping; Qi, Jia; Yamaguchi, Tsuyoshi; Wang, Hui-Ling; Morales, Marisela
Heterogeneous composition of dopamine neurons of the rat A10 region: molecular evidence for diverse signaling properties. Journal Article
In: Brain Struct Funct, vol. 218, no. 5, pp. 1159–1176, 2013, ISSN: 1863-2661 (Electronic); 1863-2653 (Linking).
@article{Li2013,
title = {Heterogeneous composition of dopamine neurons of the rat A10 region: molecular evidence for diverse signaling properties.},
author = {Xueping Li and Jia Qi and Tsuyoshi Yamaguchi and Hui-Ling Wang and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/22926514},
doi = {10.1007/s00429-012-0452-z},
issn = {1863-2661 (Electronic); 1863-2653 (Linking)},
year = {2013},
date = {2013-09-01},
journal = {Brain Struct Funct},
volume = {218},
number = {5},
pages = {1159--1176},
address = {Neuronal Networks Section, Intramural Research Program, National Institute On Drug Abuse, 251 Bayview Boulevard, Baltimore, MD 21224, USA.},
abstract = {The A10 region contains different neurons: dopamine (expressing tyrosine hydroxylase; TH), GABA, glutamate-only (expressing the vesicular glutamate transporter 2; VGluT2), and TH-VGluT2 (coexpressing TH and VGluT2). We used three methods to investigate proteins necessary for the synthesis (aromatic L-amino acid decarboxylase, AADC) or transport (vesicular monoamine transporter; VMAT2 or dopamine transporter; DAT) of dopamine within TH neurons in the A10 region. By in situ hybridization-immunohistochemistry, we found that all TH neurons in the A10 region had AADC, but not all had VMAT2, DAT or D2 receptors (D2R). To determine whether TH-VGluT2 neurons account for TH neurons lacking these dopamine markers, we implemented an anatomical "mirror technique", and found that not all TH-VGluT2 neurons lacked VMAT2, DAT or D2R. Next, by quantitative RT-PCR of individual micro-dissected TH neurons, we discovered two classes of TH-VGluT2 and three classes of TH-only neurons with different latero-medial distribution. Some of the TH-VGluT2 neurons had both VMAT2 and DAT (TH-VGluT2 Class 1); others lacked detectable levels of both transporters (TH-VGluT2 Class 2). Most of the TH-only neurons contained VMAT2 and DAT (TH-only Class 1), a few had DAT without detectable VMAT2 (TH-only Class 2), and others lacked detectable levels of both transporters (TH-only Class 3). We concluded that (a) the majority of TH neurons lacking DAT are TH-VGluT2 neurons, (b) very few TH-only neurons express DAT without VMAT2, and (c) TH-VGluT2 neurons lacking DAT also lack VMAT2. Thus, the A10 region contains dopamine neurons with differential compartmentalization and unique signaling properties.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The A10 region contains different neurons: dopamine (expressing tyrosine hydroxylase; TH), GABA, glutamate-only (expressing the vesicular glutamate transporter 2; VGluT2), and TH-VGluT2 (coexpressing TH and VGluT2). We used three methods to investigate proteins necessary for the synthesis (aromatic L-amino acid decarboxylase, AADC) or transport (vesicular monoamine transporter; VMAT2 or dopamine transporter; DAT) of dopamine within TH neurons in the A10 region. By in situ hybridization-immunohistochemistry, we found that all TH neurons in the A10 region had AADC, but not all had VMAT2, DAT or D2 receptors (D2R). To determine whether TH-VGluT2 neurons account for TH neurons lacking these dopamine markers, we implemented an anatomical "mirror technique", and found that not all TH-VGluT2 neurons lacked VMAT2, DAT or D2R. Next, by quantitative RT-PCR of individual micro-dissected TH neurons, we discovered two classes of TH-VGluT2 and three classes of TH-only neurons with different latero-medial distribution. Some of the TH-VGluT2 neurons had both VMAT2 and DAT (TH-VGluT2 Class 1); others lacked detectable levels of both transporters (TH-VGluT2 Class 2). Most of the TH-only neurons contained VMAT2 and DAT (TH-only Class 1), a few had DAT without detectable VMAT2 (TH-only Class 2), and others lacked detectable levels of both transporters (TH-only Class 3). We concluded that (a) the majority of TH neurons lacking DAT are TH-VGluT2 neurons, (b) very few TH-only neurons express DAT without VMAT2, and (c) TH-VGluT2 neurons lacking DAT also lack VMAT2. Thus, the A10 region contains dopamine neurons with differential compartmentalization and unique signaling properties.
