Available alternative incentives modulate anticipatory nucleus accumbens activation.
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ABSTRACT:
SUBMITTER: Cooper JC
PROVIDER: S-EPMC2799954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Environmental reward-predictive cues can motivate reward-seeking behaviors. Although this influence is normally adaptive, it can become maladaptive in disordered states, such as addiction. Dopamine release in the nucleus accumbens core (NAc) is known to mediate the motivational impact of reward-predictive cues, but little is known about how other neuromodulatory systems contribute to cue-motivated behavior. Here, we examined the role of the NAc cholinergic receptor system in cue-motivated behavior using a Pavlovian-to-instrumental transfer task designed to assess the motivating influence of a reward-predictive cue over an independently-trained instrumental action. Disruption of NAc muscarinic acetylcholine receptor activity attenuated, whereas blockade of nicotinic receptors augmented cue-induced invigoration of reward seeking. We next examined a potential dopaminergic mechanism for this behavioral effect by combining fast-scan cyclic voltammetry with local pharmacological acetylcholine receptor manipulation. The data show evidence of opposing modulation of cue-evoked dopamine release, with muscarinic and nicotinic receptor antagonists causing suppression and augmentation, respectively, consistent with the behavioral effects of these manipulations. In addition to demonstrating cholinergic modulation of naturally-evoked and behaviorally-relevant dopamine signaling, these data suggest that NAc cholinergic receptors may gate the expression of cue-motivated behavior through modulation of phasic dopamine release.
| S-EPMC5061892 | biostudies-other
Project description:Contemporary society is saturated with negative representations of racial and ethnic minorities. Social science research finds that exposure to such negative stereotypes creates stress above and beyond pre-existing effects of income inequality and structural racism. Neuroscience studies in animals and humans show that life stress modulates brain responses to rewards. However, it is not known whether contending with negative representations of one's social group spills overs to influence reward processing. We used functional magnetic resonance imaging to examine the effects of stigmatizing negative stereotypes on neural responding to the anticipation and consumption of monetary gains and losses in a Mexican American sample. Machine learning analyses indicated that incentive-related patterns of brain activity within the nucleus accumbens differed between Mexican Americans subjected to negative stereotypes and those who were not. This effect occurred for anticipating both gains and losses. Our work suggests that rhetoric stigmatizing Latinos and other minorities could alter how members of such groups process incentives in their environment. These findings contribute to our understanding of the linkage between stigmatizing experiences and motivated behavior, with implications for well-being and health.
| S-EPMC7235954 | biostudies-literature
Project description:Recent evidence has implicated the endocannabinoid (eCB) system in nicotine addiction. The eCB system also has an important role in reward mechanisms, and nicotine addiction has been associated with aberrant reward processing. Motivated by this evidence, we tested the hypothesis that eCB modulation of reward processing is altered in subjects with a nicotine addiction (NAD). For this purpose, we compared reward-related activity in NAD with healthy controls (HC) in a pharmacological magnetic resonance imaging (MRI) study using ?(9)-tetrahydrocannabinol (THC) administration to challenge the eCB system. Eleven HC and 10 NAD participated in a 3-T functional MRI (fMRI) study with a double-blind, cross-over, placebo-controlled design, using a Monetary Incentive Delay (MID) paradigm with three reward levels. Reward activity in the nucleus accumbens (NAcc) and caudate putamen during anticipation and feedback of reward was compared after THC and placebo. fMRI results indicated a significant reduction of reward anticipation activity in the NAcc in NAD after THC administration, which was not present in HC. This is indicated by a significant group by drug by reward interaction. Our data show that THC significantly reduces the NAcc response to monetary reward anticipation in NAD. These results suggest that nicotine addiction is associated with altered eCB modulation of reward processing in the NAcc. This study adds important human data to existing evidence implicating the eCB system in nicotine addiction.
| S-EPMC3590996 | biostudies-literature
Project description:Different accounts of nucleus accumbens (NAcc) function have emphasized its role in representing either valence or salience during incentive anticipation. In an event-related FMRI experiment, we independently manipulated valence and salience by cuing participants to anticipate certain and uncertain monetary gains and losses. NAcc activation correlated with both valence and salience. On trials with certain outcomes, NAcc activation increased for anticipated gains and decreased for anticipated losses. On trials with uncertain outcomes, NAcc activation increased for both anticipated gains and losses but did not differ between them. These findings suggest that NAcc activation separately represents both valence and salience, consistent with its hypothesized role in appetitive motivation.
| S-EPMC2169259 | biostudies-literature
Project description:Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with G? subunits, the G?5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc.
| S-EPMC4059906 | biostudies-other
Project description:BACKGROUND:Lasting changes in gene expression in brain reward regions, including nucleus accumbens (NAc), contribute to persistent functional changes in the addicted brain. We and others have demonstrated that altered expression of several candidate transcription factors in NAc regulates drug responses. A recent large-scale genome-wide study from our group predicted transcription factor E2F3 (E2F3) as a prominent upstream regulator of cocaine-induced changes in gene expression and alternative splicing. METHODS:We studied expression of two E2F3 isoforms-E2F3a and E2F3b-in mouse NAc after repeated cocaine administration and assayed the effects of overexpression or depletion of E2f3 isoforms in NAc on cocaine behavioral responses. We then performed RNA sequencing to investigate the effect of E2f3a overexpression in this region on gene expression and alternative splicing and performed quantitative chromatin immunoprecipitation at downstream targets in NAc following E2f3a overexpression or repeated cocaine exposure. Sample sizes varied between experiments and are noted in the text. RESULTS:We showed that E2f3a, but not E2f3b, overexpression or knockdown in mouse NAc regulates cocaine-induced locomotor and place conditioning behavior. Furthermore, we demonstrated that E2f3a overexpression substantially recapitulates genome-wide transcriptional profiles and alternative splicing induced by cocaine. We further validated direct binding of E2F3a at key target genes following cocaine exposure. CONCLUSIONS:This study establishes E2F3a as a novel transcriptional regulator of cocaine action in NAc. The findings reveal a crucial role for E2F3a in the regulation of cocaine-elicited behavioral states. Moreover, the importance of this role is bolstered by the extensive recapitulation of cocaine's transcriptional effects in NAc by overexpression of E2f3a.
| S-EPMC5988910 | biostudies-literature
Project description:Sign-tracking is a conditioned response where animals interact with reward-predictive cues due to the cues having motivational value, or incentive salience. The nucleus accumbens core (NAc) has been implicated in mediating the sign-tracking response. Additionally, acetylcholine (ACh) transmission throughout the striatum has been attributed to both incentive motivation and behavioral flexibility. Here, we demonstrate a role for NAc ACh receptors in the flexibility of sign-tracking. Sign-tracking animals were exposed to an omission contingency, in which vigorous sign-tracking was punished by reward omission. Animals rapidly adjusted their behavior, but they maintained sign-tracking in a less vigorous manner that did not cancel reward. Within this context of sign-tracking being persistent yet flexible in structure, blockade of NAc nicotinic receptors (nAChRs) led to a persistence in the initial sign-tracking response during omission followed by a period of change in the makeup of sign-tracking, whereas blockade of muscarinic receptors (mAChRs) oppositely enhanced the omission-related development of the new sign-tracking behaviors. Later, once omission learning had occurred, nAChR blockade uniquely led to reduced sign-tracking and elevated reward-directed behaviors instead. These results indicate that NAc ACh receptors have opposing roles in maintaining learned patterns of sign-tracking, with nAChRs having a special involvement in regulating the structure of the sign-tracking response.
| S-EPMC10435540 | biostudies-literature
Project description:How can music-merely a stream of sounds-be enjoyable for so many people? Recent accounts of this phenomenon are inspired by predictive coding models, hypothesizing that both confirmation and violations of musical expectations associate with the hedonic response to music via recruitment of the mesolimbic system and its connections with the auditory cortex. Here we provide support for this model, by revealing associations of music-induced pleasantness with musical surprises in the activity and connectivity patterns of the nucleus accumbens (NAcc)-a central component of the mesolimbic system. We examined neurobehavioral responses to surprises in three naturalistic musical pieces using fMRI and subjective ratings of valence and arousal. Surprises were associated with changes in reported valence and arousal, as well as with enhanced activations in the auditory cortex, insula and ventral striatum, relative to unsurprising events. Importantly, we found that surprise-related activation in the NAcc was more pronounced among individuals who experienced greater music-induced pleasantness. These participants also exhibited stronger surprise-related NAcc-auditory cortex connectivity during the most pleasant piece, relative to participants who found the music less pleasant. These findings provide a novel demonstration of a direct link between musical surprises, NAcc activation and music-induced pleasantness.
| S-EPMC6523415 | biostudies-literature
Project description:Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior.
| S-EPMC4200494 | biostudies-literature
Project description:A withdrawal-associated impairment in ?-endorphin neurotransmission in the arcuate nucleus (ARC) of the hypothalamus is associated with alcohol dependence characterized by a chronic relapsing disorder. Although acupuncture activates ?-endorphin neurons in the ARC projecting to the nucleus accumbens (NAc), a role for ARC ?-endorphin neurons in alcohol dependence and acupuncture effects has not been examined. Here, we show that acupuncture at Shenmen (HT7) points attenuates behavioral manifestation of alcohol dependence by activating endorphinergic input to the NAc from the ARC. Acupuncture attenuated ethanol withdrawal tremor, anxiety-like behaviors, and ethanol self-administration in ethanol-dependent rats, which are mimicked by local injection of ?-endorphin into the NAc. Acupuncture also reversed the decreased ?-endorphin levels in the NAc and a reduction of neuronal activity in the ARC during ethanol withdrawal. These results suggest that acupuncture may provide a novel, potential treatment strategy for alcohol use disorder by direct activation of the brain pathway.
| S-EPMC6726441 | biostudies-literature