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Concept: Nucleus accumbens

240

Sleep control is ascribed to a two-process model, a widely accepted concept that posits homoeostatic drive and a circadian process as the major sleep-regulating factors. Cognitive and emotional factors also influence sleep-wake behaviour; however, the precise circuit mechanisms underlying their effects on sleep control are unknown. Previous studies suggest that adenosine has a role affecting behavioural arousal in the nucleus accumbens (NAc), a brain area critical for reinforcement and reward. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound. In addition, motivational stimuli inhibit the activity of ventral pallidum-projecting NAc indirect pathway neurons and suppress sleep. Our findings reveal a prominent contribution of this indirect pathway to sleep control associated with motivation.In addition to circadian and homoeostatic drives, motivational levels influence sleep-wake cycles. Here the authors demonstrate that adenosine receptor-expressing neurons in the nucleus accumbens core that project to the ventral pallidum are inhibited by motivational stimuli and are causally involved in the control of slow-wave sleep.

Concepts: Ventral tegmental area, Basal ganglia, Substantia nigra, Globus pallidus, Striatum, Dopamine, Mesolimbic pathway, Nucleus accumbens

208

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(-/-) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(-/-) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

Concepts: Ventral tegmental area, Drug addiction, Addiction, Striatum, Dopamine, Mesolimbic pathway, Nucleus accumbens, Reward system

191

Our reputation is important to us; we’ve experienced natural selection to care about our reputation. Recently, the neural processing of gains in reputation (positive social feedback concerning one’s character) has been shown to occur in the human ventral striatum. It is still unclear, however, how individual differences in the processing of gains in reputation may lead to individual differences in real-world behavior. For example, in the real-world, one way that people currently maintain their reputation is by using social media websites, like Facebook. Furthermore, Facebook use consists of a social comparison component, where users observe others' behavior and can compare it to their own. Therefore, we hypothesized a relationship between the way the brain processes specifically self-relevant gains in reputation and one’s degree of Facebook use. We recorded functional neuroimaging data while participants received gains in reputation, observed the gains in reputation of another person, or received monetary reward. We demonstrate that across participants, when responding to gains in reputation for the self, relative to observing gains for others, reward-related activity in the left nucleus accumbens predicts Facebook use. However, nucleus accumbens activity in response to monetary reward did not predict Facebook use. Finally, a control step-wise regression analysis showed that Facebook use primarily explains our results in the nucleus accumbens. Overall, our results demonstrate how individual sensitivity of the nucleus accumbens to the receipt of self-relevant social information leads to differences in real-world behavior.

Concepts: Scientific method, Ventral tegmental area, Observation, Hypothesis, Striatum, Nucleus accumbens, Social media, Ventral striatum

170

Neuroimaging studies using positron emission tomography suggest that reduced dopamine D(2) receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D(3) receptors (D(3)Rs) in the neurobiology of addiction remains unclear, however. Here we report that D(3)R KO (D(3)(-/-)) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D(3)(-/-) mice. In addition, D(3)(-/-) mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D(3)R deletion increases vulnerability to cocaine, and that reduced D(3)R availability in the brain may constitute a risk factor for the development of cocaine addiction.

Concepts: Ventral tegmental area, Positron emission tomography, Substantia nigra, Drug addiction, Dopamine, Nucleus accumbens, Putamen, Cocaine

155

Reward hypersensitization is a common feature of neuropsychiatric disorders, manifesting as impulsivity for anticipated incentives. Temporally specific changes in activity within the nucleus accumbens (NAc), which occur during anticipatory periods preceding consummatory behavior, represent a critical opportunity for intervention. However, no available therapy is capable of automatically sensing and therapeutically responding to this vulnerable moment in time when anticipation-related neural signals may be present. To identify translatable biomarkers for an off-the-shelf responsive neurostimulation system, we record local field potentials from the NAc of mice and a human anticipating conventional rewards. We find increased power in 1- to 4-Hz oscillations predominate during reward anticipation, which can effectively trigger neurostimulation that reduces consummatory behavior in mice sensitized to highly palatable food. Similar oscillations are present in human NAc during reward anticipation, highlighting the translational potential of our findings in the development of a treatment for a major unmet need.

Concepts: Psychology, Ventral tegmental area, Motivation, Human behavior, Dopamine, Mesolimbic pathway, Nucleus accumbens, Reward

115

This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with “temperament,” including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor.

Concepts: DNA, Ventral tegmental area, Gene expression, Basal ganglia, Substantia nigra, Dopamine, Nucleus accumbens, Cocaine

65

Humans devote 30-40% of speech output solely to informing others of their own subjective experiences. What drives this propensity for disclosure? Here, we test recent theories that individuals place high subjective value on opportunities to communicate their thoughts and feelings to others and that doing so engages neural and cognitive mechanisms associated with reward. Five studies provided support for this hypothesis. Self-disclosure was strongly associated with increased activation in brain regions that form the mesolimbic dopamine system, including the nucleus accumbens and ventral tegmental area. Moreover, individuals were willing to forgo money to disclose about the self. Two additional studies demonstrated that these effects stemmed from the independent value that individuals placed on self-referential thought and on simply sharing information with others. Together, these findings suggest that the human tendency to convey information about personal experience may arise from the intrinsic value associated with self-disclosure.

Concepts: Psychology, Ventral tegmental area, Basal ganglia, Striatum, Dopamine, Mesolimbic pathway, Nucleus accumbens, Amphetamine

57

The biological mechanisms underlying long-term partner bonds in humans are unclear. The evolutionarily conserved neuropeptide oxytocin (OXT) is associated with the formation of partner bonds in some species via interactions with brain dopamine reward systems. However, whether it plays a similar role in humans has as yet not been established. Here, we report the results of a discovery and a replication study, each involving a double-blind, placebo-controlled, within-subject, pharmaco-functional MRI experiment with 20 heterosexual pair-bonded male volunteers. In both experiments, intranasal OXT treatment (24 IU) made subjects perceive their female partner’s face as more attractive compared with unfamiliar women but had no effect on the attractiveness of other familiar women. This enhanced positive partner bias was paralleled by an increased response to partner stimuli compared with unfamiliar women in brain reward regions including the ventral tegmental area and the nucleus accumbens (NAcc). In the left NAcc, OXT even augmented the neural response to the partner compared with a familiar woman, indicating that this finding is partner-bond specific rather than due to familiarity. Taken together, our results suggest that OXT could contribute to romantic bonds in men by enhancing their partner’s attractiveness and reward value compared with other women.

Concepts: Ventral tegmental area, Female, Basal ganglia, Dopamine, Mesolimbic pathway, Nucleus accumbens, Amphetamine, Reward system

55

It has been proposed that the acquisition of drug seeking is related to the development of conditioned dopamine responses in the ventral striatum. As drug use continues and becomes habit-like, conditioned responses have been shown to shift to the dorsal striatum. Here, using the PET [(11)C]raclopride method and highly personalized cocaine cues, we report the first evidence in humans of the dorsal dopamine response prior to the onset of addiction.

Concepts: Ventral tegmental area, Nicotine, Parkinson's disease, Substantia nigra, Drug addiction, Striatum, Dopamine, Nucleus accumbens

52

Glucagon-like peptide-1 (GLP-1) and its analogs act as appetite suppressants and have been proven to be clinically efficacious in reducing body weight in obese individuals. Central GLP-1 is expressed in a small population of brainstem cells located in the nucleus tractus solitarius (NTS), which project to a wide range of brain areas. However, it remains unclear how endogenous GLP-1 released in the brain contributes to appetite regulation. Using chemogenetic tools, we discovered that central GLP-1 acts on the midbrain ventral tegmental area (VTA) and suppresses high-fat food intake. We used integrated pathway tracing and synaptic physiology to further demonstrate that activation of GLP-1 receptors specifically reduces the excitatory synaptic strength of dopamine (DA) neurons within the VTA that project to the nucleus accumbens (NAc) medial shell. These data suggest that GLP-1 released from NTS neurons can reduce highly palatable food intake by suppressing mesolimbic DA signaling.

Concepts: Nervous system, Ventral tegmental area, Neuroanatomy, Basal ganglia, Appetite, Dopamine, Mesolimbic pathway, Nucleus accumbens