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Phasic dopamine release from mid-brain dopaminergic neurons is thought to signal errors of reward prediction (RPE). If reward maximisation is to maintain homeostasis, then the value of primary rewards should be coupled to the homeostatic errors they remediate. This leads to the prediction that RPE signals should be configured as a function of homeostatic state and thus diminish with the attenuation of homeostatic error. To test this hypothesis, we collected a large volume of functional MRI data from five human volunteers on four separate days. After fasting for 12 hours, subjects consumed preloads that differed in glucose concentration. Participants then underwent a Pavlovian cue-conditioning paradigm in which the colour of a fixation-cross was stochastically associated with the delivery of water or glucose via a gustometer. This design afforded computation of RPE separately for better- and worse-than expected outcomes during ascending and descending trajectories of serum glucose fluctuations. In the parabrachial nuclei, regional activity coding positive RPEs scaled positively with serum glucose for both ascending and descending glucose levels. The ventral tegmental area and substantia nigra became more sensitive to negative RPEs when glucose levels were ascending. Together, the results suggest that RPE signals in key brainstem structures are modulated by homeostatic trajectories of naturally occurring glycaemic flux, revealing a tight interplay between homeostatic state and the neural encoding of primary reward in the human brain.

Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks.

The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression—major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior. Markovic et al. demonstrate in rodents that anhedonia-like states in inflammatory pain are mediated through increased inhibitory control and subsequent diminished activity of mesolimbic dopamine neurons.

Yu, Li et al. show that VTA GABA and glutamate neurons induce sleep and waking, respectively, via projections to the lateral hypothalamus and nucleus accumbens. Thus, in addition to influencing reward-directed behaviors, the VTA regulates arousal.

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement 1 . Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement 2 , 3 (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs 4 . Among the opioid receptors, µ-opioid receptors have a key role 5 , yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation. Experiments using fentanyl treatment of mice show that µ-opioid receptors mediate positive reinforcement in the ventral tegmental area and negative reinforcement in central amygdala, thereby identifying the circuits that lead to opioid addiction.

The authors show that rostral ventral pallidum projections to the ventral tegmental area (VTA) are activated during cue-induced reinstatement of cocaine seeking, and DREADD inhibition of these projections blocks this behavior. In contrast, projections from the caudal ventral pallidum are necessary for cocaine-primed, but not cue-induced, reinstatement of cocaine seeking. The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking—a rat model of relapse in addiction. Moreover, designer receptor–mediated transient inactivation of RVP neurons, their terminals in VTA or functional connectivity between RVP and VTA dopamine neurons blocked the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition blocked cocaine-primed, but not cue-induced, reinstatement. This double dissociation in ventral pallidum subregional roles in drug seeking is likely to be important for understanding the mesocorticolimbic circuits underlying reward seeking and addiction.

A brain circuit is identified through which serotonin induces an anxiety-like state; this circuit also mediates the anxiety-like behaviour induced by acute administration of the selective serotonin reuptake inhibitor fluoxetine and may underlie the early adverse events that some patients with anxiety disorders have to these types of drugs. Serotonin-induced anxiety and fear learning The circuits through which serotonin regulates mood are not well understood. Here Thomas Kash and colleagues describe a mechanism by which serotonin induces an anxiety-like state in mice. They show that serotonergic projections from the dorsal raphe nuclei to the bed nucleus of the stria terminalis (BNST), a forebrain structure involved in controlling autonomic, neuroendocrine and behavioural responses, activate corticotropin-releasing factor (CRF) neurons that inhibit anxiolytic outputs from the BNST to the ventral tegmental area and lateral hypothalamus. They further show that this circuit mediates anxiety-like behaviour induced by acute administration of the serotonin reuptake inhibitor (SSRI) fluoxetine. The authors suggest that a similar mechanism may underlie the early adverse reactions to SSRI treatment that have been shown to occur in some patients with anxiety disorders. Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT DRN ) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF BNST ) in mice. Specifically, 5-HT DRN projections to the BNST, via actions at 5-HT 2C receptors (5-HT 2C Rs), engage a CRF BNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF BNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF 1 R, also known as CRHR1), given that CRF 1 R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT DRN →CRF BNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders 1 , 2 .

Fast-acting neurotransmitters and slow, modulatory neuropeptides are co-released from neurons in the central nervous system, albeit from distinct synaptic vesicles 1 . The mechanisms of how co-released neurotransmitters and neuropeptides that have opposing actions—for example, stimulatory versus inhibitory—work together to exert control of neural circuit output remain unclear. This has been difficult to resolve owing to the inability to selectively isolate these signalling pathways in a cell- and circuit-specific manner. Here we developed a genetic-based anatomical disconnect procedure that utilizes distinct DNA recombinases to independently facilitate CRISPR–Cas9 mutagenesis 2 of neurotransmitter- and neuropeptide-related genes in distinct cell types in two different brain regions simultaneously. We demonstrate that neurons within the lateral hypothalamus that produce the stimulatory neuropeptide neurotensin and the inhibitory neurotransmitter GABA (γ-aminobutyric acid) utilize these signals to coordinately activate dopamine-producing neurons of the ventral tegmental area. We show that GABA release from lateral hypothalamus neurotensin neurons inhibits GABA neurons within the ventral tegmental area, disinhibiting dopamine neurons and causing a rapid rise in calcium, whereas neurotensin directly generates a slow inactivating calcium signal in dopamine neurons that is dependent on the expression of neurotensin receptor 1 (Ntsr1). We further show that these two signals work together to regulate dopamine neuron responses to maximize behavioural responding. Thus, a neurotransmitter and a neuropeptide with opposing signals can act on distinct timescales through different cell types to enhance circuit output and optimize behaviour. CRISPR–Cas9 mutagenesis studies in mice demonstrate co-release of a neurotransmitter and a neuropeptide with opposing signals that stimulate the ventral tegmental area dopamine system through coordinated actions on different cells at different time scales.

Morphine is a highly potent analgesic with high addictive potential in specific contexts. Although dopamine neurons of the ventral tegmental area (VTA) are widely believed to play an essential role in the development of drug addiction, neuronal circuits underlying morphine action on dopamine neurons have not been fully elucidated. Here we combined in vivo electrophysiology, tract-tracing experiments, and targeted neuronal inactivation to dissect a neural circuit for acute morphine action on dopamine neurons in rats. We found that in vivo, morphine targets the GABAergic tail of the VTA, also called the rostromedial tegmental nucleus, to increase the firing of dopamine neurons through the activation of VTA μ opioid receptors expressed on tail of the VTA/rostromedial tegmental nucleus efferents. Our data also reveal that in the absence of VTA glutamatergic tone, there is no morphine-induced activation of dopamine neurons. These results define the anatomical organization and functional role of a neural circuit for acute morphine action on dopamine neurons.

Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K + ) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K + channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms. Potassium channels in the ventral tegmental area are known to regulate resilience against stress-induced depression. Here, the authors show over expression of KCNQ3 channels in VTA dopaminergic neurons or treatment with KCNQ channel openers normalizes depressive behaviours in mouse models.