Ventral tegmental area glutamate neurons mediate nonassociative consequences of stress

McGovern, Dillon J.; Ly, Annie; Ecton, Koy L.; Huynh, David T.; Prevost, Emily D; Gonzalez, Shamira C.; McNulty, Connor; Rau, Andrew R.; Hentges, Shane T.; Daigle, Tanya L.; Tasic, Bosiljka; Baratta, Michael V.; Root, David H.

doi:10.1038/s41380-022-01858-3

Cited by 10 publications

(19 citation statements)

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“…Given that VTA VGluT2 GCaMP signal was increased by opioid-seeking behavior, we expressed the inhibitory designer receptor hM4Di or a fluorophore control in VTA VGluT2 neurons. We delivered a behaviorally subthreshold dose of clozapine[27], which we previously showed significantly reduces hM4Di-VGluT2 neuronal activity[25], during oxycodone self-administration or cue-induced reinstatement ( Figure 5A-B ). In male mice, chemogenetic inhibition of VTA VGluT2 neurons did not modify oxycodone consumption F(2,63)=1.218, p=0.3020 ( Figure 5C ).…”

Section: Resultsmentioning

confidence: 99%

“…Mice were given three days in between each injection. GRABDA was excited at two wavelengths (465 nm and 405 nm control) with amplitude-modulated signals from two light-emitting diodes reflected off dichroic mirrors and then coupled into an optic fiber [25]. Signals from GRABDA and the control channel were returned through the same optic fiber and acquired with a femtowatt photo-receiver (Newport, Irvine, CA), digitized at 1kHz, and then recorded by a real-time signal processor (TDT).…”

Section: Discussionmentioning

confidence: 99%

“…Male and female VGluT2-IRES::Cre mice were injected in VTA with AAV8-hSyn-DIO-hM4Di-mCherry or AAV5-hSyn-DIO-GFP four weeks prior to behavioral testing, similar to prior experiments examining the roles of VTA VGluT2 neurons in motivated behavior [25]. Mice self-administered oxycodone or water as described.…”

Section: Chemogenetic Inhibition Of Vta Glutamate Neurons During Oxyc...mentioning

confidence: 99%

“…However, after three days of self-administration at the highest dose, mice received an IP injection of a behaviorally-subthreshold [27] dose of clozapine (0.1 mg/kg) ten minutes prior to self-administration. This dose has previously been shown to decrease VTA VGluT2 neuron activity [25]. After the clozapine session, three additional days of training at 1 mg/mL commenced to compare self-administration before and after chemogenetic manipulation of VTA VGluT2 neurons.…”

Section: Chemogenetic Inhibition Of Vta Glutamate Neurons During Oxyc...mentioning

confidence: 99%

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Ventral Tegmental Area Glutamate Neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate prescription opioid-seeking behavior

McGovern

Polter

et al. 2022

Preprint

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A two-neuron model of ventral tegmental area (VTA) opioid function classically involves VTA GABA neuron regulation of VTA dopamine neurons via a mu-opioid receptor dependent inhibitory circuit. However, this model predates the discovery of a third major type of neuron in the VTA: glutamatergic neurons. We find that about one-quarter of VTA neurons expressing the mu-opioid receptor are glutamate neurons without molecular markers of GABA co-release. Glutamate-Mu opioid receptor neurons are topographically distributed in the anterior VTA. The majority of remaining VTA mu-opioid receptor neurons are GABAergic neurons that are largely within the posterior VTA and do not express molecular markers of glutamate co-release. Optogenetic stimulation of VTA glutamate neurons results in monosynaptic excitatory currents recorded from VTA dopamine neurons that are reduced by presynaptic activation of the mu-opioid receptor ex vivo, establishing a local mu-opioid receptor dependent excitatory circuit from VTA glutamate neurons to VTA dopamine neurons. This VTA glutamate to VTA dopamine pathway regulates dopamine release to the nucleus accumbens through mu-opioid receptor activity in vivo. Behaviorally, VTA glutamate calcium-related neuronal activity increased following oxycodone consumption and response-contingent oxycodone-associated cues during self-administration and abstinent reinstatement of drug-seeking behavior. Further, chemogenetic inhibition of VTA glutamate neurons reduced abstinent oxycodone-seeking behavior in male but not female mice. These results establish 1) a three-neuron model of VTA opioid function involving a mu-opioid receptor gated VTA glutamate neuron pathway to VTA dopamine neurons that controls dopamine release within the nucleus accumbens, and 2) that VTA glutamate neurons participate in prescription opioid-seeking behavior.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Chemogenetic Inhibition Of Vta Glutamate Neurons During Oxyc...mentioning

confidence: 99%

Section: Chemogenetic Inhibition Of Vta Glutamate Neurons During Oxyc...mentioning

confidence: 99%

See 2 more Smart Citations

Ventral Tegmental Area Glutamate Neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate prescription opioid-seeking behavior

McGovern

Polter

et al. 2022

Preprint

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“…Using monosynaptic rabies viral tracing of inputs to VGluT2+VGaT+ neurons, we found that most synaptic inputs arose from subcortical structures implicated in motor actions, outcome valuation, and threat responding, such as superior colliculus, lateral hypothalamus, lateral habenula, periaqueductal gray, dorsal raphe, substantia innominata/ventral pallidum, locally within the VTA, and parabrachial nucleus 6,19,[38][39][40][41][42][43][44][45][46][47][48][49][50][51] . These circuits likely contribute to the high sensitivity of VTA VGluT2+VGaT+ neurons toward stressful stimuli that result in social and exploratory deficits in mice 52 . On the whole, brain-wide inputs to VTA VGluT2+VGaT+ neurons were similar to those found examining all VTA VGluT2+ neuron inputs 33,35 .…”

Section: Discussionmentioning

confidence: 99%

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

Prevost

Phillips

Lauridsen

et al. 2023

Preprint

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A unique population of ventral tegmental area (VTA) neurons co-transmits glutamate and GABA as well as functionally signals rewarding and aversive outcomes. However, the circuit inputs to VTA VGluT2+VGaT+ neurons are unknown, limiting our understanding of the functional capabilities of these neurons. To identify the inputs to VTA VGluT2+VGaT+ neurons, we coupled monosynaptic rabies tracing with intersectional genetic targeting of VTA VGluT2+VGaT+ neurons in mice. We found that VTA VGluT2+VGaT+ neurons received diverse brain-wide inputs. The largest numbers of monosynaptic inputs to VTA VGluT2+VGaT+ neurons were from superior colliculus, lateral hypothalamus, midbrain reticular nucleus, and periaqueductal gray, whereas the densest inputs relative to brain region volume were from dorsal raphe nucleus, lateral habenula, and ventral tegmental area. Based on these and prior data, we hypothesized that lateral hypothalamus and superior colliculus inputs were glutamatergic neurons. Optical activation of glutamatergic lateral hypothalamus neurons robustly activated VTA VGluT2+VGaT+ neurons regardless of stimulation frequency and resulted in flee-like ambulatory behavior. In contrast, optical activation of glutamatergic superior colliculus neurons activated VTA VGluT2+VGaT+ neurons for a brief period of time at high stimulation frequency and resulted in head rotation and arrested ambulatory behavior (freezing). For both pathways, behaviors induced by stimulation were uncorrelated with VTA VGluT2+VGaT+ neuron activity, suggesting that VGluT2+VGaT+ neurons are integrators of signals related to aversive outcomes but not of aversion-induced behavioral kinematics. We interpret these results such that VTA VGluT2+VGaT+ neurons may integrate diverse inputs related to the detection and processing of motivationally-salient outcomes.

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Spatial transcriptomic analysis of the mouse brain following chronic social defeat stress

Wang,

Song,

Zhao

et al. 2023

Exploration

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Depression is a highly prevalent and disabling mental disorder, involving numerous genetic changes that are associated with abnormal functions in multiple regions of the brain. However, there is little transcriptomic‐wide characterization of chronic social defeat stress (CSDS) to comprehensively compare the transcriptional changes in multiple brain regions. Spatial transcriptomics (ST) was used to reveal the spatial difference of gene expression in the control, resilient (RES) and susceptible (SUS) mouse brains, and annotated eight anatomical brain regions and six cell types. The gene expression profiles uncovered that CSDS leads to gene synchrony changes in different brain regions. Then it was identified that inhibitory neurons and synaptic functions in multiple regions were primarily affected by CSDS. The brain regions Hippocampus (HIP), Isocortex, and Amygdala (AMY) present more pronounced transcriptional changes in genes associated with depressive psychiatric disorders than other regions. Signalling communication between these three brain regions may play a critical role in susceptibility to CSDS. Taken together, this study provides important new insights into CSDS susceptibility at the ST level, which offers a new approach for understanding and treating depression.

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Ventral tegmental area glutamate neurons mediate nonassociative consequences of stress

Cited by 10 publications

References 64 publications

Ventral Tegmental Area Glutamate Neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate prescription opioid-seeking behavior

Ventral Tegmental Area Glutamate Neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate prescription opioid-seeking behavior

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

Spatial transcriptomic analysis of the mouse brain following chronic social defeat stress

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