Synaptic Adaptations at the Rostromedial Tegmental Nucleus Underlie Individual Differences in Cocaine Avoidance Behavior.

Although cocaine is powerfully rewarding, not all individuals are equally prone to abusing this drug. We postulate that these differences arise in part because some individuals exhibit stronger aversive responses to cocaine that protect them from cocaine seeking. Indeed, using conditioned place preference (CPP) and a runway operant cocaine self-administration task, we demonstrate that avoidance responses to cocaine vary greatly between individual high cocaine-avoider and low cocaine-avoider rats. These behavioral differences correlated with cocaine-induced activation of the rostromedial tegmental nucleus (RMTg), measured using both in vivo firing and c-fos, whereas slice electrophysiological recordings from ventral tegmental area (VTA)-projecting RMTg neurons showed that relative to low avoiders, high avoiders exhibited greater intrinsic excitability, greater transmission via calcium-permeable AMPA receptors (CP-AMPARs), and higher presynaptic glutamate release. In behaving animals, blocking CP-AMPARs in the RMTg with NASPM reduced cocaine avoidance. Hence, cocaine addiction vulnerability may be linked to multiple coordinated synaptic differences in VTA-projecting RMTg neurons.SIGNIFICANCE STATEMENT Although cocaine is highly addictive, not all individuals exposed to cocaine progress to chronic use for reasons that remain unclear. We find that cocaine's aversive effects, although less widely studied than its rewarding effects, show more individual variability, are predictive of subsequent propensity to seek cocaine, and are driven by variations in RMTg in response to cocaine that arise from distinct alterations in intrinsic excitability and glutamate transmission onto VTA-projecting RMTg neurons.

Entopeduncular Nucleus Projections to the Lateral Habenula Contribute to Cocaine Avoidance.

The aversive properties associated with drugs of abuse influence both the development of addiction and relapse. Cocaine produces strong aversive effects after rewarding effects wear off, accompanied by increased firing in the lateral habenula (LHb) that contributes to downstream activation of the rostromedial tegmental nucleus (RMTg). However, the sources of this LHb activation are unknown, as the LHb receives many excitatory inputs whose contributions to cocaine aversion remain uncharacterized. Using cFos activation and in vivo electrophysiology in male rats, we demonstrated that the rostral entopeduncular nucleus (rEPN) was the most responsive region to cocaine among LHb afferents examined and that single cocaine infusions induced biphasic responses in rEPN neurons, with inhibition during cocaine's initial rewarding phase transitioning to excitation during cocaine's delayed aversive phase. Furthermore, rEPN lesions reduced cocaine-induced cFos activation by 2-fold in the LHb and by a smaller proportion in the RMTg, while inactivation of the rEPN or the rEPN-LHb pathway attenuated cocaine avoidance behaviors measured by an operant runway task and by conditioned place aversion (CPA). These data show an essential but not exclusive role of rEPN and its projections to the LHb in processing the aversive effects of cocaine, which could serve as a novel target for addiction vulnerability.SIGNIFICANCE STATEMENT Cocaine produces well-known rewarding effects but also strong aversive effects that influence addiction propensity, but whose mechanisms are poorly understood. We had previously reported that the lateral habenula (LHb) is activated by cocaine and contributes to cocaine's aversive effects, and the current findings show that the rostral entopeduncular nucleus (rEPN) is a major contributor to this LHb activation and to conditioned avoidance of cocaine. These findings show a critical, though not exclusive, rEPN role in cocaine's aversive effects, and shed light on the development of addiction.

Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity.

Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.

The ventrolateral periaqueductal grey updates fear via positive prediction error.

Aversive, positive prediction error (+PE) provides a mechanism to update and increase future fear to uncertain threat predictors. The ventrolateral periaqueductal grey (vlPAG) has been offered as a neural locus for +PE computation. Yet, a causal demonstration of vlPAG +PE activity to update fear remains elusive. We devised a fear discrimination procedure in which a danger cue predicts shock deterministically and an uncertainty cue predicts shock probabilistically, requiring prediction errors to achieve an appropriate fear response. Recording vlPAG single-unit activity during fear discrimination in Long-Evans rats, we reveal activity related to shock is consistent with +PE and updates subsequent fear to uncertainty at the trial level. We further demonstrate that vlPAG inhibition during shock selectively decreases future fear to uncertainty, but not danger, and temporal emergence of this effect is consistent with single-unit activity. These findings provide causal evidence that vlPAG +PE is necessary for fear updating.

Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat.

Development of new treatments for drug addiction will depend on high-throughput screening in animal models. However, an addiction biomarker fit for rapid testing, and useful in both humans and animals, is not currently available. Economic models are promising candidates. They offer a structured quantitative approach to modeling behavior that is mathematically identical across species, and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity. However, economic demand has not yet been established as a biomarker of addiction-like behavior in animals, an essential final step in linking animal and human studies of addiction through economic models. We recently developed a mathematical approach for rapidly modeling economic demand in rats trained to self-administer cocaine. We show here that economic demand, as both a spontaneous trait and induced state, predicts addiction-like behavior, including relapse propensity, drug seeking in abstinence, and compulsive (punished) drug taking. These findings confirm economic demand as a biomarker of addiction-like behavior in rats. They also support the view that excessive motivation plays an important role in addiction while extending the idea that drug dependence represents a shift from initially recreational to compulsive drug use. Finally, we found that economic demand for cocaine predicted the efficacy of a promising pharmacotherapy (oxytocin) in attenuating cocaine-seeking behaviors across individuals, demonstrating that economic measures may be used to rapidly identify the clinical utility of prospective addiction treatments.

Role for the Rostromedial Tegmental Nucleus in Signaling the Aversive Properties of Alcohol.

BACKGROUND: While the rewarding effects of alcohol contribute significantly to its addictive potential, it is becoming increasingly appreciated that alcohol's aversive properties also play an important role in the propensity to drink. Despite this, the neurobiological mechanism for alcohol's aversive actions is not well understood. The rostromedial tegmental nucleus (RMTg) was recently characterized for its involvement in aversive signaling and has been shown to encode the aversive properties of cocaine, yet its involvement in alcohol's aversive actions have not been elucidated. METHODS: Adult male and female Long-Evans rats underwent conditioned taste aversion (CTA) procedures where exposure to a novel saccharin solution was paired with intraperitoneal administration of saline, lithium chloride (LiCl), or ethanol (EtOH). Control rats underwent the same paradigm except that drug and saccharin exposure were explicitly unpaired. Saccharin consumption was measured on test day in the absence of drug administration, and rats were sacrificed 90 to 105 minutes following access to saccharin. Brains were subsequently harvested and processed for cFos immunohistochemistry. The number of cFos-labeled neurons was counted in the RMTg and the lateral habenula (LHb)-a region that sends prominent glutamatergic input to the RMTg. RESULTS: In rats that received paired drug and saccharin exposure, EtOH and LiCl induced significant CTA compared to saline to a similar degree in males and females. Both EtOH- and LiCl-induced CTA significantly enhanced cFos expression in the RMTg and LHb but not the hippocampus. Similar to behavioral measures, no significant effect of sex on CTA-induced cFos expression was observed. cFos expression in both the RMTg and LHb was significantly correlated with CTA magnitude with greater cFos being associated with more pronounced CTA. In addition, cFos expression in the RMTg was positively correlated with LHb cFos. CONCLUSIONS: These data suggest that the RMTg and LHb are involved in the expression of CTA and are consistent with previous work implicating the RMTg in aversive signaling. Furthermore, increased cFos expression in the RMTg following EtOH-induced CTA suggests that this region plays a role in signaling alcohol's aversive properties.

Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways.

Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. Using electrophysiological recordings in awake rats, we found that some neurons in the lateral habenula (LHb), where activation produces aversive conditioning, exhibited biphasic responses to single doses of intravenous cocaine, with an initial inhibition followed by delayed excitation paralleling cocaine's shift from rewarding to aversive. Recordings in LHb slice preparations revealed similar cocaine-induced biphasic responses and further demonstrated that biphasic responses were mimicked by dopamine, that the inhibitory phase depended on dopamine D2-like receptors, and that the delayed excitation persisted after drug washout for prolonged durations consistent with findings in vivo. c-Fos experiments further showed that cocaine-activated LHb neurons preferentially projected to and activated neurons in the rostromedial tegmental nucleus (RMTg), a recently identified target of LHb axons that is activated by negative motivational stimuli and inhibits dopamine neurons. Finally, pharmacological excitation of the RMTg produced conditioned place aversion, whereas cocaine-induced avoidance behaviors in a runway operant paradigm were abolished by lesions of LHb efferents, lesions of the RMTg, or by optogenetic inactivation of the RMTg selectively during the period when LHb neurons are activated by cocaine. Together, these results indicate that LHb/RMTg pathways contribute critically to cocaine-induced avoidance behaviors, while also participating in reciprocally inhibitory interactions with dopamine neurons.

Substantia Nigra Dopamine Neuronal Responses to Habenular Stimulation and Foot Shock Are Altered by Lesions of the Rostromedial Tegmental Nucleus.

Dopamine (DA) neurons of the substantia nigra (SN) and ventral tegmental area generally respond to aversive stimuli or the absence of expected rewards with transient inhibition of firing rates, which can be recapitulated with activation of the lateral habenula (LHb) and eliminated by lesioning the intermediating rostromedial tegmental nucleus (RMTg). However, a minority of DA neurons respond to aversive stimuli, such as foot shock, with a transient increase in firing rate, an outcome that rarely occurs with LHb stimulation. The degree to which individual neurons respond to these two stimulation modalities with the same response phenotype and the role of the RMTg is not known. Here, we record responses from single SN DA neurons to alternating activation of the LHb and foot shock in male rats. Lesions of the RMTg resulted in a shift away from inhibition to no response during both foot shock and LHb stimulation. Furthermore, lesions unmasked an excitatory response during LHb stimulation. The response correspondence within the same neuron between the two activation sources was no different from chance in sham controls, suggesting that external inputs rather than intrinsic DA neuronal properties are more important to response outcome. These findings contribute to a literature that shows a complex neurocircuitry underlies the regulation of DA activity and, by extension, behaviors related to learning, anhedonia, and cognition.

Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions.

A new mesopontine structure exerting a strong influence on dopamine systems has recently been defined: the tail of the ventral tegmental area/rostromedial tegmental nucleus (tVTA/RMTg). This review presents a neuroanatomical, physiological, and behavioral overview of some of the recent and ongoing research on this brain region and its relationship with dopamine systems. The tVTA/RMTg sends dense GABA projections to VTA and substantia nigra neurons. The inhibitory influence of tVTA/RMTg on dopamine neurons is supported by both neuroanatomical and electrophysiology data. The latter studies also reveal the tVTA/RMTg as a substrate for morphine and cannabinoid action on dopamine cells. In primates, the tVTA/RMTg has been implicated in reward prediction error signals, through a basal ganglia-lateral habenula-tVTA/RMTg-dopamine-basal ganglia circuit. In rodents, the tVTA/RMTg has been shown to play a critical role in aversive behaviors, particularly those involving behavioral inhibition, such as freezing and avoidance. These findings highlight the functional importance of the tVTA/RMTg as a major GABA brake for dopamine systems.

Innate cocaine-seeking vulnerability arising from loss of serotonin-mediated aversive effects of cocaine in rats.

Cocaine blocks dopamine reuptake, thereby producing rewarding effects that are widely studied. However, cocaine also blocks serotonin uptake, which we show drives, in rats, individually variable aversive effects that depend on serotonin 2C receptors (5-HT2CRs) in the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons. 5-HT2CRs produce depolarizing effects in RMTg neurons that are particularly strong in some rats, leading to aversive effects that reduce acquisition of and relapse to cocaine seeking. In contrast, 5-HT2CR signaling is largely lost after cocaine exposure in other rats, leading to reduced aversive effects and increased cocaine seeking. These results suggest a serotonergic biological marker of cocaine-seeking vulnerability that can be targeted to modulate drug seeking.

Pumping the brakes: rostromedial tegmental inhibition of compulsive cocaine seeking.

Addiction is marked by aberrant decision-making and an inability to suppress inappropriate and often dangerous behaviors. We previously demonstrated that inactivation of the rostromedial tegmental nucleus (RMTg) in rats causes persistent food seeking despite impending aversive footshock, an effect strikingly similar to the punishment resistance observed in people with a history of protracted drug use [1]. Here, we extend these studies to demonstrate chemogenetic silencing of RMTg axonal projections to the ventral tegmental area (VTA) (RMTg→VTA pathway) causes rats to endure significantly more footshock to receive cocaine infusions. To further test whether activation of this circuit is sufficient to suppress reward seeking in the absence of an overtly aversive stimulus, we used temporally specific optogenetic stimulation of the RMTg→VTA pathway as a "punisher" in place of footshock following lever pressing for either food or cocaine reward. While optical stimulation of the RMTg→VTA pathway robustly suppressed lever pressing for food, we found that stimulation of this circuit had only modest effects on suppressing responding for cocaine infusions. Even though optical RMTg→VTA stimulation was not particularly effective at reducing ongoing cocaine use, this experience nevertheless had long-lasting consequences, as reinstatement of drug seeking in response to cocaine-associated cues was profoundly suppressed when tested nearly two weeks later. These results suggest the RMTg may serve as a useful target for producing enduring reductions in drug craving, particularly during periods of abstinence from drug use.

Heroin Self-Administration and Extinction Increase Prelimbic Cortical Astrocyte-Synapse Proximity and Alter Dendritic Spine Morphometrics That Are Reversed by N-Acetylcysteine.

Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astrocyte glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observe functional adaptations in the PrL cortical astrocyte following heroin self-administration (SA) and extinction as measured by the electrophysiologically evoked plasmalemmal glutamate transporter 1 (GLT-1)-dependent current. We likewise observed the increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astrocytic plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astrocytic complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased the apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague-Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased the co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, the accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Finally, we show that the NAC treatment and elimination of thrombospondin 2 (TSP-2) block cue-induced heroin relapse. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at the synapses. Additionally, these data demonstrate that NAC reverses PrL cortical heroin SA-and-extinction-induced adaptations in both astrocytes and corticostriatal neurons.

A wireless and battery-less implant for multimodal closed-loop neuromodulation in small animals.

Fully implantable wireless systems for the recording and modulation of neural circuits that do not require physical tethers or batteries allow for studies that demand the use of unconstrained and freely behaving animals in isolation or in social groups. Moreover, feedback-control algorithms that can be executed within such devices without the need for remote computing eliminate virtual tethers and any associated latencies. Here we report a wireless and battery-less technology of this type, implanted subdermally along the back of freely moving small animals, for the autonomous recording of electroencephalograms, electromyograms and body temperature, and for closed-loop neuromodulation via optogenetics and pharmacology. The device incorporates a system-on-a-chip with Bluetooth Low Energy for data transmission and a compressed deep-learning module for autonomous operation, that offers neurorecording capabilities matching those of gold-standard wired systems. We also show the use of the implant in studies of sleep-wake regulation and for the programmable closed-loop pharmacological suppression of epileptic seizures via feedback from electroencephalography. The technology can support a broader range of applications in neuroscience and in biomedical research with small animals.

Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates.

Lateral habenula (LHb) neurons signal negative "reward-prediction errors" and inhibit midbrain dopamine (DA) neurons. Yet LHb neurons are largely glutamatergic, indicating that this inhibition may occur through an intermediate structure. Recent studies in rats have suggested a candidate for this role, the GABAergic rostromedial tegmental nucleus (RMTg), but this neural pathway has not yet been tested directly. We now show using electrophysiology and anatomic tracing that (1) the monkey has an inhibitory structure similar to the rat RMTg; (2) RMTg neurons receive excitatory input from the LHb, exhibit negative reward-prediction errors, and send axonal projections near DA soma; and (3) stimulating this structure inhibits DA neurons. Surprisingly, some RMTg neurons responded to reward cues earlier than the LHb, and carry "state-value" signals not found in DA neurons. Thus, our data suggest that the RMTg translates LHb reward-prediction errors (negative) into DA reward-prediction errors (positive), while transmitting additional motivational signals to non-DA networks.

Linking drug and food addiction via compulsive appetite.

BACKGROUND AND PURPOSE: 'Food addiction' is the subject of intense public and research interest. However, this nosology based on neurobehavioural similarities among obese individuals, patients with eating disorders and those with substance use disorders (drug addiction) remains controversial. We thus sought to determine which aspects of disordered eating are causally linked to preclinical models of drug addiction. We hypothesized that extensive drug histories, known to cause addiction-like brain changes and drug motivation in rats, would also cause addiction-like food motivation. EXPERIMENTAL APPROACH: Rats underwent extensive cocaine, alcohol, caffeine or obesogenic diet histories and were subsequently tested for punishment-resistant food self-administration or 'compulsive appetite', as a measure of addiction-like food motivation. KEY RESULTS: Extensive cocaine and alcohol (but not caffeine) histories caused compulsive appetite that persisted long after the last drug exposure. Extensive obesogenic diet histories also caused compulsive appetite, although neither cocaine nor alcohol histories caused excess calorie intake and bodyweight during abstinence. Hence, compulsive appetite and obesity appear to be dissociable, with the former sharing common mechanisms with preclinical drug addiction models. CONCLUSION AND IMPLICATIONS: Compulsive appetite, as seen in subsets of obese individuals and patients with binge-eating disorder and bulimia nervosa (eating disorders that do not necessarily result in obesity), appears to epitomize 'food addiction'. Because different drug and obesogenic diet histories caused compulsive appetite, overlapping dysregulations in the reward circuits, which control drug and food motivation independently of energy homeostasis, may offer common therapeutic targets for treating addictive behaviours across drug addiction, eating disorders and obesity.

An opioid-gated thalamoaccumbal circuit for the suppression of reward seeking in mice.

Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. In a mouse model using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream neurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamic µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids.

The rostromedial tegmental (RMTg) "brake" on dopamine and behavior: A decade of progress but also much unfinished work.

Between 2005 and 2009, several research groups identified a strikingly dense inhibitory input to midbrain dopamine neurons arising from a previously uncharted region posterior to the ventral tegmental area (VTA). This region is now denoted as either the rostromedial tegmental nucleus (RMTg) or the "tail of the VTA" (tVTA), and is recognized to express distinct genetic markers, encode negative "prediction errors" (inverse to dopamine neurons), and play critical roles in behavioral inhibition and punishment learning. RMTg neurons are also influenced by many categories of abused drugs, and may drive some aversive responses to such drugs, particularly cocaine and alcohol. However, despite much progress, many important questions remain about RMTg molecular/genetic properties, diversity of projection targets, and applications to addiction, depression, and other neuropsychiatric disorders. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.

Prelimbic cortical projections to rostromedial tegmental nucleus play a suppressive role in cue-induced reinstatement of cocaine seeking.

The prelimbic (PL) region of prefrontal cortex has been implicated in both driving and suppressing cocaine seeking in animal models of addiction. We hypothesized that these opposing roles for PL may be supported by distinct efferent projections. While PL projections to nucleus accumbens core have been shown to be involved in driving reinstatement of cocaine seeking, PL projections to the rostromedial tegmental nucleus (RMTg) may instead suppress reinstatement of cocaine seeking, due to the role of RMTg in behavioral inhibition. Here, we used a functional disconnection approach to temporarily disrupt the PL-RMTg pathway during cue- or cocaine-induced reinstatement. Male Sprague Dawley rats self-administered cocaine during daily 2-h sessions for ≥10 days and then underwent extinction training. Reinstatement of extinguished cocaine seeking was elicited by cocaine-associated cues or cocaine prime. Prior to reinstatement, rats received microinjections of the GABA agonists baclofen/muscimol (1/0.1 mM) into unilateral PL and the AMPA receptor antagonist NBQX (1 mM) into contralateral or ipsilateral RMTg. Functional disconnection of PL-RMTg via contralateral inactivation markedly increased cue-induced reinstatement, but did not increase cocaine-induced reinstatement or drive reinstatement of extinguished cocaine seeking in the absence of cues or cocaine. Enhanced cue-induced reinstatement was also observed with ipsilateral inactivation of PL and RMTg, but not with unilateral inactivation of PL or RMTg alone, indicating that both ipsilateral and contralateral projections from PL to RMTg have an inhibitory influence on behavior. These data further support a suppressive role for PL in cocaine seeking by implicating PL efferent projections to RMTg in inhibiting cue-induced reinstatement.

Bidirectional Valence Encoding in the Ventral Pallidum.

In this issue of Neuron, Stephenson-Jones et al. (2020) dissect the function of the enigmatic ventral pallidum and elegantly demonstrate positive and negative valence encoding in its GABA and glutamate neurons that influence both approach and avoidance behavior via the lateral habenula.

The Rostromedial Tegmental Nucleus: Anatomical Studies and Roles in Sleep and Substance Addictions in Rats and Mice.

The rostromedial tegmental nucleus (RMTg), a brake of the dopamine system, is specifically activated by aversive stimuli, such as foot shock. It is principally composed of gamma-aminobutyric acid neurons. However, there is no exact location of the RMTg on the brain stereotaxic atlas. The RMTg can be defined by c-Fos staining elicited by psychostimulants, the position of retrograde-labeled neurons stained by injections into the ventral tegmental area (VTA), the terminal field formed by axons from the lateral habenula, and some molecular markers identified as specifically expressed in the RMTg such as FoxP1. The RMTg receives a broad range of inputs and produces diverse outputs, which indicates that the RMTg has multiple functions. First, the RMTg plays an essential role for non-rapid eye movement sleep. Additionally, the RMTg serves a vital role in response to addiction. Opiates increase the firing rates of dopaminergic neurons in the VTA by acting on µ-opioid receptors on RMTg neurons and their terminals inside the VTA. In this review, we summarize the recent research advances on the anatomical location of the RMTg in rats and mice, its projections, and its regulation of sleep-wake behavior and addiction.