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

eLife ◽  
2018 ◽  
Vol 7 ◽  
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.

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

2015 ◽  
Vol 114 (3) ◽  
pp. 1734-1745 ◽  
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.

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

2021 ◽  
Author(s):  
Linda Requie ◽  
Marta Gómez-Gonzalo ◽  
Francesca Managò ◽  
Mauro Congiu ◽  
Marcello Melone ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Activation ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Astrocytic Process ◽  
Metabotropic Glutamate ◽  
Ventral Tegmental

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.

scholarly journals Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults

2012 ◽  
Vol 108 (6) ◽  
pp. 1620-1630 ◽  
Author(s):  
James E. McCutcheon ◽  
Kelly L. Conrad ◽  
Steven B. Carr ◽  
Kerstin A. Ford ◽  
Daniel S. McGehee ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Drug Addiction ◽  
Brain Slices ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Membrane Properties ◽  
Neuron Firing ◽  
Postsynaptic Currents ◽  
Adolescent Rats ◽  
Ventral Tegmental

Adolescence may be a period of vulnerability to drug addiction. In rats, elevated firing activity of ventral tegmental area (VTA) dopamine neurons predicts enhanced addiction liability. Our aim was to determine if dopamine neurons are more active in adolescents than in adults and to examine mechanisms underlying any age-related difference. VTA dopamine neurons fired faster in adolescents than in adults as measured with in vivo extracellular recordings. Dopamine neuron firing can be divided into nonbursting (single spikes) and bursting activity (clusters of high-frequency spikes). Nonbursting activity was higher in adolescents compared with adults. Frequency of burst events did not differ between ages, but bursts were longer in adolescents than in adults. Elevated dopamine neuron firing in adolescent rats was also observed in cell-attached recordings in ex vivo brain slices. Using whole cell recordings, we found that passive and active membrane properties were similar across ages. Hyperpolarization-activated cation currents and small-conductance calcium-activated potassium channel currents were also comparable across ages. We found no difference in dopamine D2-class autoreceptor function across ages, although the high baseline firing in adolescents resulted in autoreceptor activation being less effective at silencing neurons. Finally, AMPA receptor-mediated spontaneous excitatory postsynaptic currents occurred at lower frequency in adolescents; GABAA receptor-mediated spontaneous inhibitory postsynaptic currents occurred at both lower frequency and smaller amplitude in adolescents. In conclusion, VTA dopamine neurons fire faster in adolescence, potentially because GABA tone increases as rats reach adulthood. This elevation of firing rate during adolescence is consistent with it representing a vulnerable period for developing drug addiction.

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

2018 ◽  
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.

scholarly journals Control of the Nigrostriatal Dopamine Neuron Activity and Motor Function by the Tail of the Ventral Tegmental Area

2014 ◽  
Vol 39 (12) ◽  
pp. 2788-2798 ◽  
Author(s):  
Romain Bourdy ◽  
María-José Sánchez-Catalán ◽  
Jennifer Kaufling ◽  
Judith J Balcita-Pedicino ◽  
Marie-José Freund-Mercier ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Motor Function ◽  
Dopamine Neuron ◽  
Neuron Activity ◽  
Nigrostriatal Dopamine ◽  
Ventral Tegmental

scholarly journals Adiponectin modulates ventral tegmental area dopamine neuron activity and anxiety-related behavior through AdipoR1

2018 ◽  
Vol 24 (1) ◽  
pp. 126-144 ◽  
Author(s):  
Fengjiao Sun ◽  
Yun Lei ◽  
Jingjing You ◽  
Chen Li ◽  
Linshan Sun ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Dopamine Neuron ◽  
Neuron Activity ◽  
Ventral Tegmental

scholarly journals Ventral Tegmental Area GABA, glutamate, and glutamate-GABA neurons are heterogenous in their electrophysiological and pharmacological properties

2020 ◽  
Author(s):  
Jorge Miranda-Barrientos ◽  
Ian Chambers ◽  
Smriti Mongia ◽  
Bing Liu ◽  
Hui-Ling Wang ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Viral Vectors ◽  
Ex Vivo ◽  
Glutamate Transporter ◽  
Receptor Activation ◽  
Firing Frequency ◽  
Dopamine Neurons ◽  
Gaba Neurons ◽  
Double Transgenic Mouse ◽  
Ventral Tegmental

AbstractThe ventral tegmental area (VTA) contains dopamine neurons intermixed with GABA-releasing (expressing vesicular GABA transporter, VGaT), glutamate-releasing (expressing vesicular glutamate transporter, VGluT2), and co-releasing (co-expressing VGaT and VGluT2) neurons. By delivering INTRSECT viral vectors into VTA of double vglut2-Cre/vgat-Flp transgenic mice, we targeted specific VTA cell populations for ex vivo recordings. We found that VGluT2+ VGaT− and VGluT2+ VGaT+ neurons on average had relatively hyperpolarized resting membrane voltage, greater rheobase, and lower spontaneous firing frequency compared to VGluT2− VGaT+ neurons, suggesting that VTA glutamate-releasing and glutamate-GABA co-releasing neurons require stronger excitatory drive to fire than GABA-releasing neurons. In addition, we detected expression of Oprm1mRNA (encoding μ opioid receptors, MOR) in VGluT2+ VGaT− and VGluT2− VGaT+ neurons, and their hyperpolarization by the MOR agonist DAMGO. Collectively, we demonstrate the utility of the double transgenic mouse to access VTA glutamate, glutamate-GABA and GABA neurons, and show some electrophysiological heterogeneity among them.Impact StatementSome physiological properties of VTA glutamate-releasing and glutamate-GABA co-releasing neurons are distinct from those of VTA GABA-releasing neurons. μ-opioid receptor activation hyperpolarizes some VTA glutamate-releasing and some GABA-releasing neurons.

scholarly journals Hippocampal α5-GABAA receptors modulate dopamine neuron activity in the rat ventral tegmental area

2022 ◽  
Author(s):  
Stephanie M. Perez ◽  
Alexandra M. McCoy ◽  
Thomas D. Prevot ◽  
Yeunus Mian ◽  
Flavia R. Carreno ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Gabaa Receptors ◽  
Dopamine Neuron ◽  
Neuron Activity ◽  
Ventral Tegmental
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