Long-lasting synaptic regulation of dopamine neurons by astrocytes in the Ventral Tegmental Area

Abstract The plasticity of glutamatergic transmission in the Ventral Tegmental Area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and the phasic dopamine release at VTA target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated-behaviors. Here we describe a hitherto unidentified mechanism of long-lasting potentiation of glutamatergic synapses on DA neurons. We found that VTA astrocytes respond to dopamine neuron bursts with Ca2+ elevations that require activation of endocannabinoid CB1 and dopamine D2 receptors colocalized at the same astrocytic process. Astrocytes, in turn, release glutamate that, through presynaptic metabotropic glutamate receptor activation coupled with neuronal nitric oxide production, induces long-lasting potentiation of excitatory synapses on adjacent dopamine neurons. Consistent with this finding, selective activation of VTA astrocytes increases dopamine neuron bursts in vivo and induces locomotor hyperactivity. Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron activity.

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Neurotensin inhibits both dopamine- and GABA-mediated inhibition of ventral tegmental area dopamine neurons

Journal of Neurophysiology ◽

10.1152/jn.00279.2015 ◽

2015 ◽

Vol 114 (3) ◽

pp. 1734-1745 ◽

Cited By ~ 18

Author(s):

Katherine Stuhrman ◽

Aaron G. Roseberry

Keyword(s):

Ventral Tegmental Area ◽

Calcium Release ◽

Transient Receptor Potential ◽

Brain Slices ◽

Receptor Activation ◽

Dopamine Neuron ◽

Dopamine Neurons ◽

Neuron Activity ◽

Inward Current ◽

Ventral Tegmental

Dopamine is an essential neurotransmitter that plays an important role in a number of different physiological processes and disorders. There is substantial evidence that the neuropeptide neurotensin interacts with the mesolimbic dopamine system and can regulate dopamine neuron activity. In these studies we have used whole cell patch-clamp electrophysiology in brain slices from mice to examine how neurotensin regulates dopamine neuron activity by examining the effect of neurotensin on the inhibitory postsynaptic current generated by somatodendritic dopamine release (D2R IPSC) in ventral tegmental area (VTA) dopamine neurons. Neurotensin inhibited the D2R IPSC and activated an inward current in VTA dopamine neurons that appeared to be at least partially mediated by activation of a transient receptor potential C-type channel. Neither the inward current nor the inhibition of the D2R IPSC was affected by blocking PKC or calcium release from intracellular stores, and the inhibition of the D2R IPSC was greater with neurotensin compared with activation of other Gq-coupled receptors. Interestingly, the effects of neurotensin were not specific to D2R signaling as neurotensin also inhibited GABAB inhibitory postsynaptic currents in VTA dopamine neurons. Finally, the effects of neurotensin were significantly larger when intracellular Ca2+ was strongly buffered, suggesting that reduced intracellular calcium facilitates these effects. Overall these results suggest that neurotensin may inhibit the D2R and GABAB IPSCs downstream of receptor activation, potentially through regulation of G protein-coupled inwardly rectifying potassium channels. These studies provide an important advance in our understanding of dopamine neuron activity and how it is controlled by neurotensin.

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HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

eLife ◽

10.7554/elife.32420 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 20

Author(s):

Peng Zhong ◽

Casey R Vickstrom ◽

Xiaojie Liu ◽

Ying Hu ◽

Laikang Yu ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Chronic Stress ◽

Ex Vivo ◽

Critical Role ◽

Dopamine Neuron ◽

Dopamine Neurons ◽

Neuron Activity ◽

Hcn Channels ◽

Neuron Firing ◽

Ventral Tegmental

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.

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Slow Oscillatory Firing: A Major Firing Pattern of Dopamine Neurons in the Ventral Tegmental Area

Journal of Neurophysiology ◽

10.1152/jn.00317.2005 ◽

2005 ◽

Vol 94 (5) ◽

pp. 3516-3522 ◽

Cited By ~ 30

Author(s):

Wei-Xing Shi

Keyword(s):

Ventral Tegmental Area ◽

Single Unit ◽

Firing Pattern ◽

Receptor Activation ◽

Dopamine Neurons ◽

Interspike Intervals ◽

Firing Activity ◽

Unit Recording ◽

Ventral Tegmental

Using spectral analysis and in vivo single-unit recording in rats, the present study revealed a pronounced slow oscillation (SO) in the firing activity of about half the dopamine (DA) neurons recorded in the ventral tegmental area. DA neurons in this group tended to fire repetitive spike clusters, making them appear to be rhythmic bursting cells. However, only some of these burst-like events met the traditional “80/160 ms” burst criteria entirely. The observation that the SO could be found in nonbursting DA cells, occurred at frequencies different from those of bursts, and persisted after bursts were digitally removed from spike trains further supports the suggestion that the SO is different from the traditionally defined bursting. Interspike intervals (ISIs) had been thought to be bimodally distributed in bursting DA neurons. This study found that some nonbursting DA cells also had a bimodal ISI distribution and a significant number of bursting cells did not. In the majority of cells where less than half the spikes occurred in bursts, a bimodal ISI distribution was highly predictive of the presence of the SO. Results further showed that the generation of the SO required forebrain inputs to DA neurons but not the adrenergic α1 receptor activation responsible for psychostimulant-induced increases in the SO. Taken together, these results suggest that the SO is distinct from the traditionally defined bursting and represents a major firing pattern of DA neurons in the ventral tegmental area.

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Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice

10.1101/800052 ◽

2019 ◽

Author(s):

Bertha J. Vandegrift ◽

Elisa R. Hilderbrand ◽

Rosalba Satta ◽

Rex Tai ◽

Donghong He ◽

...

Keyword(s):

Estrogen Receptor ◽

Binge Drinking ◽

Ventral Tegmental Area ◽

Alcohol Drinking ◽

Metabotropic Glutamate Receptor ◽

Dopamine Neurons ◽

Ethanol Sensitivity ◽

Female Mice ◽

Metabotropic Glutamate ◽

Ventral Tegmental

AbstractElevations in estrogen (17β-estradiol, E2) are associated with increased alcohol drinking by women and experimentally in rodents. E2 alters the activity of the dopamine system, including the ventral tegmental area (VTA) and its projection targets, which plays an important role in binge drinking. A previous study demonstrated that during high E2 states, VTA dopamine neurons in female mice are more sensitive to ethanol excitation. However, the mechanisms responsible for the ability of E2 to enhance ethanol sensitivity of VTA dopamine neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of estrogen receptor subtypes (ERα and ERβ) in regulating the ethanol sensitivity of VTA dopamine neurons and found that ERα promotes the enhanced ethanol response of VTA dopamine neurons. We also demonstrated that the E2-induced increase in ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERα at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus expressing short hairpin RNAs targeting either ERα or ERβ into the VTA and found that knockdown of each receptor in the VTA reduced binge-like ethanol drinking in female, but not male, mice. Reducing ERα in the VTA had a more dramatic effect on binge-like drinking than reducing ERβ, consistent with the ability of ERα to alter ethanol sensitivity of dopamine neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking.Significance StatementEstrogen has potent effects on the dopamine system and increases the vulnerability of females to develop addiction to substances such as cocaine and alcohol. We investigated the mechanisms by which estrogen increases the response of dopamine neurons in the ventral tegmental area to ethanol. We found that activation of the estrogen receptor, ERα, increased the ethanol-induced excitation of dopamine neurons and that this required the metabotropic glutamate receptor mGluR1. We also demonstrated that estrogen receptors in the ventral tegmental area regulate binge-like alcohol drinking by female, but not male, mice. The influence of estrogen receptors on binge drinking in female mice suggests that treatments for alcohol use disorder in women may need to account for this sex difference.

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Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

10.1101/246595 ◽

2018 ◽

Cited By ~ 1

Author(s):

Stephen V Mahler ◽

Zachary D Brodnik ◽

Brittney M Cox ◽

William C Buchta ◽

Brandon S Bentzley ◽

...

Keyword(s):

Ventral Tegmental Area ◽

G Protein ◽

Dopamine Neuron ◽

Dopamine Neurons ◽

Response Strategy ◽

Neuron Activity ◽

G Protein Signaling ◽

Protein Signaling ◽

Cocaine Seeking ◽

Ventral Tegmental

AbstractVentral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaine’s reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction.Significance StatementG-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamine’s complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

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