Re-examining the role of ventral tegmental area dopaminergic neurons in motor activity and reinforcement by chemogenetic and optogenetic manipulation in mice

Jing, Manyi; Han, Xiao; Zhao, Tai-Yun; Wang, Zhiyuan; Lu, Guan-Yi; Wu, Ning; Song, Rui; Li, Jin

doi:10.1007/s11011-019-00442-z

Cited by 20 publications

(10 citation statements)

References 34 publications

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“…The VTA plays a significant role in motor activity and locomotor sensitization (Steketee and Kalivas, 2011;Runegaard et al, 2019). Chemogenetic inhibition of VTA DA neurons reduced basal and cocaine-induced locomotion (Runegaard et al, 2018), while exciting VTA DA neurons, or the VTA-to-NAc projection, elevated basal locomotion (Boekhoudt et al, 2016;Runegaard et al, 2018;Jing et al, 2019;Mahler et al, 2019;Runegaard et al, 2019). mPFC pyramidal neurons synapse onto VTA DA neurons (Carr and Sesack, 2000;Sesack et al, 2003;Geisler and Wise, 2008) and activation of the mPFC (Murase et al, 1993;Tong et al, 1996) or intra-VTA infusion of glutamatergic agonists (Johnson et al, 1992;Chergui et al, 1993) induces burst-spiking of VTA DA neurons in vivo.…”

Section: Discussionmentioning

confidence: 99%

Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning

Rose¹,

Velasco

Vo³

et al. 2021

J. Neurosci.

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Drug-induced neuroadaptations in the mPFC have been implicated in addictive behaviors. Repeated cocaine exposure has been shown to increase pyramidal neuron excitability in the prelimbic (PL) region of the mouse mPFC, an adaptation attributable to a suppression of G protein-gated inwardly rectifying K 1 (GIRK) channel activity. After establishing that this neuroadaptation is not seen in adjacent GABA neurons, we used viral GIRK channel ablation and complementary chemogenetic approaches to selectively enhance PL pyramidal neuron excitability in adult mice, to evaluate the impact of this form of plasticity on PL-dependent behaviors. GIRK channel ablation decreased somatodendritic GABA B receptor-dependent signaling and rheobase in PL pyramidal neurons. This manipulation also enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or trace fear learning. In contrast, selective chemogenetic excitation of PL pyramidal neurons, or chemogenetic inhibition of PL GABA neurons, increased baseline and cocaine-induced activity and disrupted trace fear learning. These effects were mirrored in male mice by selective excitation of PL pyramidal neurons projecting to the VTA, but not NAc or BLA. Collectively, these data show that manipulations enhancing the excitability of PL pyramidal neurons, and specifically those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure in mice.

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Section: Discussionmentioning

confidence: 99%

Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning

Rose¹,

Velasco

Vo³

et al. 2021

J. Neurosci.

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“…One can hypothesize that these structures -as they are members of the RAS-contribute to the alterations in activity cycles found in KCNQ4 KO animals. The PPN, the raphe nuclei and the VTA are all involved in both, sleep-wakefulness and movement regulation (Jing et al, 2019;Su et al, 2019;McGuier et al, 2018;Zhao et al, 2017;Monti, 2010;MacLaren et al, 2018;Mena-Segovia and Bolam, 2017). Therefore, as it was expected, distances run under different environmental light conditions were significantly different in WT and KO animals.…”

Section: Discussionmentioning

confidence: 92%

The KCNQ4-mediated M-current regulates the circadian rhythm in mesopontine cholinergic neurons

Tsogbadrakh

Stupniki

Kovács

et al. 2020

Preprint

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The M-current is a voltage gated potassium current inhibited by muscarinic activation and affected by several other G-protein coupled receptors. Its channels are formed by KCNQ subunits, from which KCNQ4 is restricted to certain brainstem structures. We sought evidence for the function of the M-current in the pedunculopontine nucleus (PPN) and the contribution of KCNQ4 subunits to the M-current and aimed to find its functional significance in the PPN. We found that cholinergic inputs of the PPN can effectively inhibit M-current. This current is capable of synchronizing neighboring neurons and inhibition of the M-current decreases neuronal synchronization. We showed that only a subpopulation of cholinergic neurons has KCNQ4-dependent M-current. The KCNQ4 subunit expression potentially regulates the presence of other KCNQ subunits. Deletion of KCNQ4 leads to alterations in adaptation of activity to light-darkness cycles, thus representing the potential role of KCNQ4 in regulation of sleep-wakefulness cycles. The presence of this protein restricted to certain brainstem nuclei raises the possibility that it might be a potential target for selective therapeutic interventions affecting the reticular activating system.

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“…We focused on motor activity, which is known to be controlled by DA. Notably, recent studies revealed that DA neurons of the VTA, and not those of the Substantia Nigra (SN), play a major role in the induction of motor hyperactivity 3,33,34 . Locomotion in an open field arena was tested in male mice given bilateral VTA injections of AAV9-GFAP-hM3D(Gq)-mCherry (hM3D) or AAV8-GFAP-GFP (GFP) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Requie¹,

Gómez-Gonzalo²,

Managò

et al. 2021

Preprint

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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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Re-examining the role of ventral tegmental area dopaminergic neurons in motor activity and reinforcement by chemogenetic and optogenetic manipulation in mice

Cited by 20 publications

References 34 publications

Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning

Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning

The KCNQ4-mediated M-current regulates the circadian rhythm in mesopontine cholinergic neurons

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

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