The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses.
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ABSTRACT:
SUBMITTER: Jhou TC
PROVIDER: S-EPMC2841475 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The rostromedial tegmental nucleus (RMTg), also known as the tail of the ventral tegmental area (tVTA), is a GABAergic structure identified in 2009 that receives strong inputs from the lateral habenula and other sources, sends dense inhibitory projections to midbrain dopamine (DA) neurons, and plays increasingly recognized roles in aversive learning, addiction, and other motivated behaviors. In general, little is known about the genetic identity of these neurons. However, recent work has identified the transcription factor FoxP1 as enhanced in the mouse RMTg (Lahti et al. in Development 143(3):516-529, 2016). Hence, in the current study, we used RNA sequencing to identify genes significantly enhanced in the rat RMTg as compared to adjacent VTA, and then examined the detailed distribution of two genes in particular, prepronociceptin (Pnoc) and FoxP1. In rats and mice, both Pnoc and FoxP1 were expressed at high levels in the RMTg and colocalized strongly with previously established RMTg markers. FoxP1 was particularly selective for RMTg neurons, as it was absent in most adjacent brain regions. We used these gene expression patterns to refine the anatomic characterization of RMTg in rats, extend this characterization to mice, and show that optogenetic manipulation of RMTg in mice bidirectionally modulates real-time place preference. Hence, RMTg neurons in both rats and mice exhibit distinct genetic profiles that correlate with their distinct connectivity and function.
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Project description:Rapid eye movement (REM) sleep disturbances are prevalent in various psychiatric disorders. However, the neural circuits that regulate REM sleep remain poorly understood. Here, we found that in male mice, optogenetic activation of rostromedial tegmental nucleus (RMTg) GABAergic neurons immediately converted REM sleep to arousal and then initiated non-REM (NREM) sleep. Conversely, laser-mediated inactivation completely converted NREM to REM sleep and prolonged REM sleep duration. The activity of RMTg GABAergic neurons increased to a high discharge level at the termination of REM sleep. RMTg GABAergic neurons directly converted REM sleep to wakefulness and NREM sleep via inhibitory projections to the laterodorsal tegmentum (LDT) and lateral hypothalamus (LH), respectively. Furthermore, LDT glutamatergic neurons were responsible for the REM sleep-wake transitions following photostimulation of the RMTgGABA-LDT circuit. Thus, RMTg GABAergic neurons are essential for suppressing the induction and maintenance of REM sleep.
| S-EPMC9729601 | biostudies-literature
Project description:The rostromedial tegmental nucleus (RMTg) is a bilateral structure localized in the brainstem and comprise of mainly GABAergic neurons. One of the main functions of the RMTg is to regulate the activity of dopamine neurons of the mesoaccumbens pathway. Therefore, the RMTg has been proposed as a modulator of the reward system and adaptive behaviors associated to reward learning. The RMTg receives an important glutamatergic input from the lateral habenula. Also, it receives cholinergic inputs from the laterodorsal and pedunculopontine tegmental nuclei. Previously, it was reported that nicotine increases glutamate release, evoked by electric stimulation, in the RMTg nucleus. However, the mechanisms by which nicotine induces this effect were not explored. In the present work, we performed electrophysiological experiments in brainstem slices to study the effect of nicotine on spontaneous excitatory postsynaptic currents recorded from immunocytochemically identified RMTg neurons. Also, we used calcium imaging techniques to explore the effects of nicotine on multiple RMTg neurons simultaneously. We found that nicotine promotes the persistent release of glutamate through the activation of α7 nicotinic acetylcholine receptors present on glutamatergic afferents and by a mechanism involving calcium release from intracellular stores. Through these mechanisms, nicotine increases the excitability and synchronizes the activity of RMTg neurons. Our results suggest that the RMTg nucleus mediates the noxious effects of the nicotine, and it could be a potential therapeutic target against tobacco addiction.
| S-EPMC7838497 | biostudies-literature
Project description:Many general anesthetics potentiate gamma-aminobutyric acid (GABA) A receptors but their neuroanatomic sites of action are less clear. GABAergic neurons in the rostromedial tegmental nucleus (RMTg) send inhibitory projections to multiple arousal-promoting nuclei, but the role of these neurons in modulating consciousness is unknown. In this study, designer receptors exclusively activated by designer drugs (DREADDs) were targeted to RMTg GABAergic neurons of Vgat-ires-Cre mice. DREADDs expression was found in the RMTg and other brainstem regions. Activation of these neurons decreased movement and exploratory behavior, impaired motor coordination, induced electroencephalogram (EEG) oscillations resembling nonrapid eye movement (NREM) sleep without loss of righting and reduced the dose requirement for sevoflurane-induced unconsciousness. These results suggest that GABAergic neurons in the RMTg and other brainstem regions promote sedation and facilitate sevoflurane-induced unconsciousness.
| S-EPMC7969415 | biostudies-literature
Project description:Persistence of reward seeking despite punishment or other negative consequences is a defining feature of mania and addiction, and numerous brain regions have been implicated in such punishment learning, but in disparate ways that are difficult to reconcile. We now show that the ability of an aversive punisher to inhibit reward seeking depends on coordinated activity of three distinct afferents to the rostromedial tegmental nucleus (RMTg) arising from cortex, brainstem, and habenula that drive triply dissociable RMTg responses to aversive cues, outcomes, and prediction errors, respectively. These three pathways drive correspondingly dissociable aspects of punishment learning. The RMTg in turn drives negative, but not positive, valence encoding patterns in the ventral tegmental area (VTA). Hence, punishment learning involves pathways and functions that are highly distinct, yet tightly coordinated.
| S-EPMC6989096 | biostudies-literature
Project description:A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area [VTA]), has been proposed as an inhibitory control center for dopaminergic activity of the VTA. This region is composed of GABAergic cells that send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in vivo, ex vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg. This suggests that the RMTg may be a key modulator of opioid effects and a major brake regulating VTA dopamine systems. However, no study has directly manipulated RMTg GABAergic neurons in vivo and assessed the effect on nociception or opioid analgesia. In this study, multiplexing of GABAergic neurons in the RMTg was achieved using stimulatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and inhibitory kappa-opioid receptor DREADDs (KORD). Our data show that locally infused RMTg morphine or selective RMTg GABAergic neuron inhibition produces 87% of the maximal antinociceptive effect of systemic morphine, and RMTg GABAergic neurons modulate dopamine release in the nucleus accumbens. In addition, chemoactivation of VTA dopamine neurons significantly reduced pain behaviors both in resting and facilitated pain states and reduced by 75% the dose of systemic morphine required to produce maximal antinociception. These results provide compelling evidence that RMTg GABAergic neurons are involved in processing of nociceptive information and are important mediators of opioid analgesia.
| S-EPMC7343630 | biostudies-literature
Project description:The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.
| S-EPMC5919677 | biostudies-literature
Project description:Recent findings suggest that the mesolimbic dopamine neurons, known to promote cocaine-seeking behavior, are strongly inhibited by a newly characterized region of the midbrain known as the rostromedial tegmental nucleus (RMTg). The RMTg appears to be involved in generating reward-prediction error signals and inhibition of motivated behaviors, suggesting its potential involvement in the extinction of cocaine seeking as well. Therefore, to address this question, male Sprague-Dawley rats underwent surgeries for implantation of catheters and cannulas targeted at the RMTg. After cocaine self-administration, rats underwent modified extinction training. Pre- or post-training intra-RMTg microinjections of the allosteric AMPA receptor potentiator PEPA during the first 5 days of extinction training appeared to enhance the retention of the extinction learning. Following the extinction training, rats underwent cue-induced reinstatement or an 'inactivation-alone' extinction tests. RMTg inactivation before a cue-induced reinstatement session or inactivation alone before a standard extinction session increased overall lever pressing. To determine whether these effects generalized to other motivated behaviors, additional experiments examining food-seeking behavior were also conducted. The results from the food-seeking experiments indicate that PEPA microinjections into the RMTg did not influence the extinction of food seeking and that, at least in rats that had not been given PEPA during the extinction learning experiments, RMTg inactivation had no effect on lever pressing during the cue-induced reinstatement or inactivation-alone tests. These findings suggest that the RMTg provides general behavioral inhibition and is potentially involved in learning to extinguish cocaine-seeking behavior in rats.
| S-EPMC4330500 | biostudies-literature
Project description:Rostromedial tegmental nucleus (RMTg) GABA neurons exert a primary inhibitory drive onto midbrain dopamine neurons and are excited by a variety of aversive stimuli. There is, however, little evidence that the RMTg-ventral tegmental area (VTA)-nucleus accumbens shell (Acb) circuit plays a role in the aversive consequences of alcohol withdrawal. This study was performed in adult male Long-Evans rats at 48-h withdrawal from chronic alcohol drinking in the intermittent schedule. These rats displayed clear anhedonia and depression-like behaviors, as measured with the sucrose preference, and forced swimming tests. These aberrant behaviors were accompanied by a substantial increase in cFos expression in the VTA-projecting RMTg neurons, identified by a combination of immunohistochemistry and retrograde-tracing techniques. Pharmacological or chemogenetic inhibition of RMTg neurons mitigated the anhedonia and depression-like behaviors. Ex vivo electrophysiological data showed that chemogenetic inactivation of RMTg neurons reduced GABA release and accelerated spontaneous firings of VTA dopamine neurons. Finally, using a functional hemispheric disconnection procedure, we demonstrated that inhibition of unilateral RMTg, when combined with activation of D1 and D2 dopamine receptors in the contralateral (but not ipsilateral) Acb, mitigated the anhedonia and depression-like behaviors in alcohol-withdrawal rats. These data show that the integrity in the RMTg-VTA-Acb pathway in a single hemisphere is sufficient to elicit depression-like behavior during ethanol-withdrawal. Overall, the present results reveal that the RMTg-VTA-Acb pathway plays a crucial role in the depression-like behavior in animals undergoing alcohol withdrawal, further advocating the RMTg as a potential therapeutic target for alcoholism.
| S-EPMC6784902 | biostudies-literature
Project description:Acute withdrawal from alcohol is associated with a number of unpleasant symptoms that play an important role in preventing recovery and long-term abstinence. Considerable research has focused on the role that neuropeptide systems and the amygdala play in mediating affective symptoms of acute withdrawal, but promising preclinical findings have not translated successfully into the clinic. The rostromedial tegmental nucleus (RMTg) has been implicated in both fear and anxiety. In addition, RMTg neurons exert inhibitory control over midbrain dopamine neurons, the activity of which are suppressed during acute withdrawal. Thus, we hypothesized that the RMTg may play a role in mediating symptoms of acute withdrawal. Using a chronic ethanol vapor exposure paradigm that renders rats physically dependent on ethanol, we observed significant withdrawal-induced enhancement of cFos expression in the RMTg. This was accompanied by a significant increase in somatic symptoms and a decrease in reward sensitivity as measured by intracranial self-stimulation (ICSS). Both measures followed a similar time course to RMTg cFos expression with peak symptom severity occurring 12 h following cessation of ethanol exposure. Heightened anxiety-like behavior was also observed in withdrawn rats at this same time point. RMTg inhibition had no effect on somatic signs of withdrawal or withdrawal-induced changes in reward sensitivity, but significantly attenuated withdrawal-induced anxiety-like behavior. Together, these data demonstrate that the RMTg plays a distinct role in the negative affective state associated with acute withdrawal and may therefore be critically involved in the neurobiological mechanisms that promote relapse during early stages of recovery.
| S-EPMC6785010 | biostudies-literature