2025
Barbano, M Flavia; Wang, Huiling; Zhang, Shiliang; Shevelkin, Alexey V; Yu, Kevin J; Richie, Christopher T; Liu, Bing; Hahn, Suyun; Ye, Rong; Morales, Marisela
VTA monosynaptic connections by local glutamate and GABA neurons and their distinct roles in behavior Journal Article
In: Nat Commun, vol. 16, no. 1, pp. 8500, 2025, ISSN: 2041-1723.
@article{pmid41006220b,
title = {VTA monosynaptic connections by local glutamate and GABA neurons and their distinct roles in behavior},
author = {M Flavia Barbano and Huiling Wang and Shiliang Zhang and Alexey V Shevelkin and Kevin J Yu and Christopher T Richie and Bing Liu and Suyun Hahn and Rong Ye and Marisela Morales},
url = {https://pubmed.ncbi.nlm.nih.gov/41006220/},
doi = {10.1038/s41467-025-63396-0},
issn = {2041-1723},
year = {2025},
date = {2025-09-01},
urldate = {2025-09-01},
journal = {Nat Commun},
volume = {16},
number = {1},
pages = {8500},
abstract = {The ventral tegmental area (VTA) dopamine neurons have been implicated in diverse behaviors. These VTA neurons are intermixed with neurons that co-transmit glutamate and GABA (VTA), transmit glutamate (VTA) or GABA (VTA). In dual recombinase vglut2-Cre/vgat-Flp transgenic mice, we combined quantitative ultrastructural analysis with 3D correlative light and electron microscopy and found that VTA neurons frequently established synapses on VTA and VTA neurons, and that VTA neurons mostly synapsed on VTA neurons. By selective targeting of VTA subpopulations of neurons, we demonstrated that activation of VTA neurons is rewarding and decreases feeding behavior, while activation of VTA neurons is aversive. We found that activation of VTA or VTA neurons negatively affected learning to obtain food reward, and impaired cue-induced reinstatement of food-seeking behavior. Collectively, we demonstrated the monosynaptic properties of an unexpected VTA microcircuitry in which distinct neuronal components integrate information related to reward, aversion, and feeding.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The ventral tegmental area (VTA) dopamine neurons have been implicated in diverse behaviors. These VTA neurons are intermixed with neurons that co-transmit glutamate and GABA (VTA), transmit glutamate (VTA) or GABA (VTA). In dual recombinase vglut2-Cre/vgat-Flp transgenic mice, we combined quantitative ultrastructural analysis with 3D correlative light and electron microscopy and found that VTA neurons frequently established synapses on VTA and VTA neurons, and that VTA neurons mostly synapsed on VTA neurons. By selective targeting of VTA subpopulations of neurons, we demonstrated that activation of VTA neurons is rewarding and decreases feeding behavior, while activation of VTA neurons is aversive. We found that activation of VTA or VTA neurons negatively affected learning to obtain food reward, and impaired cue-induced reinstatement of food-seeking behavior. Collectively, we demonstrated the monosynaptic properties of an unexpected VTA microcircuitry in which distinct neuronal components integrate information related to reward, aversion, and feeding.
2024
Barbano, M Flavia; Qi, Jia; Chen, Emma; Mohammad, Uzma; Espinoza, Orlando; Candido, Marcos; Wang, Huiling; Liu, Bing; Hahn, Suyun; Vautier, François; Morales, Marisela
VTA glutamatergic projections to the nucleus accumbens suppress psychostimulant-seeking behavior Journal Article
In: Neuropsychopharmacology, vol. 49, no. 12, pp. 1905–1915, 2024, ISSN: 1740-634X.
@article{pmid38926603b,
title = {VTA glutamatergic projections to the nucleus accumbens suppress psychostimulant-seeking behavior},
author = {M Flavia Barbano and Jia Qi and Emma Chen and Uzma Mohammad and Orlando Espinoza and Marcos Candido and Huiling Wang and Bing Liu and Suyun Hahn and François Vautier and Marisela Morales},
url = {https://pubmed.ncbi.nlm.nih.gov/38926603/},
doi = {10.1038/s41386-024-01905-3},
issn = {1740-634X},
year = {2024},
date = {2024-11-01},
urldate = {2024-11-01},
journal = {Neuropsychopharmacology},
volume = {49},
number = {12},
pages = {1905--1915},
abstract = {Converging evidence indicates that both dopamine and glutamate neurotransmission within the nucleus accumbens (NAc) play a role in psychostimulant self-administration and relapse in rodent models. Increased NAc dopamine release from ventral tegmental area (VTA) inputs is critical to psychostimulant self-administration and NAc glutamate release from prelimbic prefrontal cortex (PFC) inputs synapsing on medium spiny neurons (MSNs) is critical to reinstatement of psychostimulant-seeking after extinction. The regulation of the activity of MSNs by VTA dopamine inputs has been extensively studied, and recent findings have demonstrated that VTA glutamate neurons target the NAc medial shell. Here, we determined whether the mesoaccumbal glutamatergic pathway plays a role in psychostimulant conditioned place preference and self-administration in mice. We used optogenetics to induce NAc release of glutamate from VTA inputs during the acquisition, expression, and reinstatement phases of cocaine- or methamphetamine-induced conditioned place preference (CPP), and during priming-induced reinstatement of cocaine-seeking behavior. We found that NAc medial shell release of glutamate resulting from the activation of VTA glutamatergic fibers did not affect the acquisition of cocaine-induced CPP, but it blocked the expression, stress- and priming-induced reinstatement of cocaine- and methamphetamine CPP, as well as it blocked the priming-induced reinstatement of cocaine-seeking behavior after extinction. These findings indicate that in contrast to the well-recognized mesoaccumbal dopamine system that is critical to psychostimulant reward and relapse, there is a parallel mesoaccumbal glutamatergic system that suppresses reward and psychostimulant-seeking behavior.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Converging evidence indicates that both dopamine and glutamate neurotransmission within the nucleus accumbens (NAc) play a role in psychostimulant self-administration and relapse in rodent models. Increased NAc dopamine release from ventral tegmental area (VTA) inputs is critical to psychostimulant self-administration and NAc glutamate release from prelimbic prefrontal cortex (PFC) inputs synapsing on medium spiny neurons (MSNs) is critical to reinstatement of psychostimulant-seeking after extinction. The regulation of the activity of MSNs by VTA dopamine inputs has been extensively studied, and recent findings have demonstrated that VTA glutamate neurons target the NAc medial shell. Here, we determined whether the mesoaccumbal glutamatergic pathway plays a role in psychostimulant conditioned place preference and self-administration in mice. We used optogenetics to induce NAc release of glutamate from VTA inputs during the acquisition, expression, and reinstatement phases of cocaine- or methamphetamine-induced conditioned place preference (CPP), and during priming-induced reinstatement of cocaine-seeking behavior. We found that NAc medial shell release of glutamate resulting from the activation of VTA glutamatergic fibers did not affect the acquisition of cocaine-induced CPP, but it blocked the expression, stress- and priming-induced reinstatement of cocaine- and methamphetamine CPP, as well as it blocked the priming-induced reinstatement of cocaine-seeking behavior after extinction. These findings indicate that in contrast to the well-recognized mesoaccumbal dopamine system that is critical to psychostimulant reward and relapse, there is a parallel mesoaccumbal glutamatergic system that suppresses reward and psychostimulant-seeking behavior.
Barbano, M Flavia; Zhang, Shiliang; Chen, Emma; Espinoza, Orlando; Mohammad, Uzma; Alvarez-Bagnarol, Yocasta; Liu, Bing; Hahn, Suyun; Morales, Marisela
Lateral hypothalamic glutamatergic inputs to VTA glutamatergic neurons mediate prioritization of innate defensive behavior over feeding Journal Article
In: Nat Commun, vol. 15, no. 1, pp. 403, 2024, ISSN: 2041-1723.
@article{pmid38195566c,
title = {Lateral hypothalamic glutamatergic inputs to VTA glutamatergic neurons mediate prioritization of innate defensive behavior over feeding},
author = {M Flavia Barbano and Shiliang Zhang and Emma Chen and Orlando Espinoza and Uzma Mohammad and Yocasta Alvarez-Bagnarol and Bing Liu and Suyun Hahn and Marisela Morales},
url = {https://pubmed.ncbi.nlm.nih.gov/38195566/},
doi = {10.1038/s41467-023-44633-w},
issn = {2041-1723},
year = {2024},
date = {2024-01-01},
urldate = {2024-01-01},
journal = {Nat Commun},
volume = {15},
number = {1},
pages = {403},
abstract = {The lateral hypothalamus (LH) is involved in feeding behavior and defense responses by interacting with different brain structures, including the Ventral Tegmental Area (VTA). Emerging evidence indicates that LH-glutamatergic neurons infrequently synapse on VTA-dopamine neurons but preferentially establish multiple synapses on VTA-glutamatergic neurons. Here, we demonstrated that LH-glutamatergic inputs to VTA promoted active avoidance, long-term aversion, and escape attempts. By testing feeding in the presence of a predator, we observed that ongoing feeding was decreased, and that this predator-induced decrease in feeding was abolished by photoinhibition of the LH-glutamatergic inputs to VTA. By VTA specific neuronal ablation, we established that predator-induced decreases in feeding were mediated by VTA-glutamatergic neurons but not by dopamine or GABA neurons. Thus, we provided evidence for an unanticipated neuronal circuitry between LH-glutamatergic inputs to VTA-glutamatergic neurons that plays a role in prioritizing escape, and in the switch from feeding to escape in mice.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The lateral hypothalamus (LH) is involved in feeding behavior and defense responses by interacting with different brain structures, including the Ventral Tegmental Area (VTA). Emerging evidence indicates that LH-glutamatergic neurons infrequently synapse on VTA-dopamine neurons but preferentially establish multiple synapses on VTA-glutamatergic neurons. Here, we demonstrated that LH-glutamatergic inputs to VTA promoted active avoidance, long-term aversion, and escape attempts. By testing feeding in the presence of a predator, we observed that ongoing feeding was decreased, and that this predator-induced decrease in feeding was abolished by photoinhibition of the LH-glutamatergic inputs to VTA. By VTA specific neuronal ablation, we established that predator-induced decreases in feeding were mediated by VTA-glutamatergic neurons but not by dopamine or GABA neurons. Thus, we provided evidence for an unanticipated neuronal circuitry between LH-glutamatergic inputs to VTA-glutamatergic neurons that plays a role in prioritizing escape, and in the switch from feeding to escape in mice.
2020
Barbano, M Flavia; Wang, Hui-Ling; Zhang, Shiliang; Miranda-Barrientos, Jorge; Estrin, David J; Figueroa-González, Almaris; Liu, Bing; Barker, David J; Morales, Marisela
VTA Glutamatergic Neurons Mediate Innate Defensive Behaviors Journal Article
In: Neuron, vol. 107, no. 2, pp. 368–382.e8, 2020, ISSN: 1097-4199.
@article{pmid32442399,
title = {VTA Glutamatergic Neurons Mediate Innate Defensive Behaviors},
author = {M Flavia Barbano and Hui-Ling Wang and Shiliang Zhang and Jorge Miranda-Barrientos and David J Estrin and Almaris Figueroa-González and Bing Liu and David J Barker and Marisela Morales},
url = {https://pubmed.ncbi.nlm.nih.gov/32442399/},
doi = {10.1016/j.neuron.2020.04.024},
issn = {1097-4199},
year = {2020},
date = {2020-07-01},
urldate = {2020-07-01},
journal = {Neuron},
volume = {107},
number = {2},
pages = {368--382.e8},
abstract = {The ventral tegmental area (VTA) has dopamine, GABA, and glutamate neurons, which have been implicated in reward and aversion. Here, we determined whether VTA-glutamate or -GABA neurons play a role in innate defensive behavior. By VTA cell-type-specific genetic ablation, we found that ablation of glutamate, but not GABA, neurons abolishes escape behavior in response to threatening stimuli. We found that escape behavior is also decreased by chemogenetic inhibition of VTA-glutamate neurons and detected increases in activity in VTA-glutamate neurons in response to the threatening stimuli. By ultrastructural and electrophysiological analysis, we established that VTA-glutamate neurons receive a major monosynaptic glutamatergic input from the lateral hypothalamic area (LHA) and found that photoinhibition of this input decreases escape responses to threatening stimuli. These findings indicate that VTA-glutamate neurons are activated by and required for innate defensive responses and that information on threatening stimuli to VTA-glutamate neurons is relayed by LHA-glutamate neurons.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The ventral tegmental area (VTA) has dopamine, GABA, and glutamate neurons, which have been implicated in reward and aversion. Here, we determined whether VTA-glutamate or -GABA neurons play a role in innate defensive behavior. By VTA cell-type-specific genetic ablation, we found that ablation of glutamate, but not GABA, neurons abolishes escape behavior in response to threatening stimuli. We found that escape behavior is also decreased by chemogenetic inhibition of VTA-glutamate neurons and detected increases in activity in VTA-glutamate neurons in response to the threatening stimuli. By ultrastructural and electrophysiological analysis, we established that VTA-glutamate neurons receive a major monosynaptic glutamatergic input from the lateral hypothalamic area (LHA) and found that photoinhibition of this input decreases escape responses to threatening stimuli. These findings indicate that VTA-glutamate neurons are activated by and required for innate defensive responses and that information on threatening stimuli to VTA-glutamate neurons is relayed by LHA-glutamate neurons.
2014
Kramar, Cecilia P; Chefer, Vladimir I; Wise, Roy A; Medina, Jorge H; Barbano, M Flavia
Dopamine in the dorsal hippocampus impairs the late consolidation of cocaine-associated memory Journal Article
In: Neuropsychopharmacology, vol. 39, no. 7, pp. 1645–1653, 2014, ISSN: 1740-634X.
@article{pmid24442095,
title = {Dopamine in the dorsal hippocampus impairs the late consolidation of cocaine-associated memory},
author = {Cecilia P Kramar and Vladimir I Chefer and Roy A Wise and Jorge H Medina and M Flavia Barbano},
url = {https://pubmed.ncbi.nlm.nih.gov/24442095/},
doi = {10.1038/npp.2014.11},
issn = {1740-634X},
year = {2014},
date = {2014-06-01},
urldate = {2014-06-01},
journal = {Neuropsychopharmacology},
volume = {39},
number = {7},
pages = {1645--1653},
abstract = {Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.
