Subregions Of Nucleus Accumbens Research Articles

Replication and extension of the subregion selectivity of glutamate-related changes within the nucleus accumbens associated with the incubation of cocaine-craving

Cue-elicited drug-seeking behavior intensifies with the passage of time during withdrawal from drug taking and this “incubation of cocaine-craving” involves alterations in nucleus accumbens (NA) glutamate transmission. Here, we employed a combination of in vivo microdialysis and immunoblotting approaches to further examine changes in biochemical indices of glutamate transmission within NA subregions that accompany the incubation of cocaine-craving exhibited by male rats with a 10-day history of 6-h access to intravenous cocaine (0.25 mg/infusion). Immunoblotting on whole cell lysates from the core subregion (NAc core) revealed interactions between cocaine self-administration history, withdrawal and drug cue re-exposure for Homer2a/b, mGlu1, and GluN2b expression, as well as indices of Akt and ERK activity. With the exception of PKCε phosphorylation, most protein changes within the shell subregion (NAc shell) depended on drug cue re-exposure and cocaine history rather than varying in a consistent time-dependent manner. Reduced basal extracellular glutamate content was apparent only in the NAc core of cocaine-experienced rats during protracted (30 days) withdrawal and this was accompanied by a markedly blunted capacity of the mGlu1/5 agonist DHPG to elevate glutamate levels within this subregion. Finally, over-expressing neither Homer1c nor Homer2b within the NAc core during protracted cocaine withdrawal altered the magnitude of cue-elicited responding, its extinction or cocaine-primed reinstatement of drug-seeking behavior. The present findings are consistent with the extant literature implicating changes in Group 1 mGlu receptor function within the NAc core subregion as central to incubated cocaine-craving and provide further evidence against a major role for Homer proteins in gating incubated cocaine-craving. Further, our results provide novel correlational evidence implicating elevated Akt and blunted ERK activity within the NAc core as potential contributors to the expression of incubated cocaine-craving, worthy of future investigation.

Altered dynamic functional connectivity of nucleus accumbens subregions in major depressive disorder: the interactive effect of childhood trauma and diagnosis.

Major depressive disorder (MDD) with childhood trauma represents a heterogeneous clinical subtype of depression. Previous research has observed alterations in the reward circuitry centered around the nucleus accumbens (NAc) in MDD patients. However, limited investigations have focused on aberrant functional connectivity (FC) within NAc subregions among MDD with childhood trauma. Thus, this study adopts analyses of both static FC (sFC) and dynamic FC (dFC) to examine neurobiological changes in MDD with childhood trauma. The bilateral nucleus accumbens shell (NAc-shell) and nucleus accumbens core (NAc-core) were selected as the seeds. Four participant groups were included: MDD with childhood trauma (n = 48), MDD without childhood trauma (n = 30), healthy controls (HCs) with childhood trauma (n = 57), and HCs without childhood trauma (n = 46). Our findings revealed both abnormal sFC and dFC between NAc-shell and NAc-core and regions including the middle occipital gyrus (MOG), anterior cingulate cortex, and inferior frontal gyrus in MDD with childhood trauma. Furthermore, a significant correlation was identified between the dFC of the left NAc-shell and the right MOG in relation to childhood trauma. Additionally, abnormal dFC moderated the link between childhood abuse and depression severity. These outcomes shed light on the neurobiological underpinnings of MDD with childhood trauma.

Nucleus accumbens sub-regions experience distinct dopamine release responses following acute and chronic morphine exposure.

The social and economic consequences of the opioid epidemic are tragic and far-reaching. Yet, opioids are indisputably necessary in clinical settings where they remain the most useful treatment for severe pain. To combat this crisis, we must improve our understanding of opioid function in the brain, particularly the neural mechanisms that underlie opioid dependence and addictive behaviors. This study uses fiber photometry to examine dopamine changes that occur in response to repeated morphine, and morphine withdrawal, at multiple stages of a longitudinal opioid-dependence paradigm. We reveal key differences in how dopamine levels respond to opioid administration in distinct sub-regions of the ventral striatum and lay a foundation for future opioid research that appreciates our contemporary understanding of the dopamine system.

Effects of MC-100093 on Ethanol Drinking and the Expression of Astrocytic Glutamate Transporters in the Mesocorticolimbic Brain Regions of Male and Female Alcohol-Preferring Rats

Chronic ethanol consumption increased extracellular glutamate concentrations in several reward brain regions. Glutamate homeostasis is regulated in majority by astrocytic glutamate transporter 1 (GLT-1) as well as the interactive role of cystine/glutamate antiporter (xCT). In this study, we aimed to determine the attenuating effects of a novel beta-lactam MC-100093, lacking the antibacterial properties, on ethanol consumption and GLT-1 and xCT expression in the subregions of nucleus accumbens (NAc core and NAc shell) and medial prefrontal cortex (Infralimbic, mPFC-IL and Prelimbic, mPFC-PL) in male and female alcohol-preferring (P) rats. Female and male rats were exposed to free access to ethanol (15% v/v) and (30% v/v) and water for five weeks, and on Week 6, rats were administered 100 mg/kg (i.p) of MC-100093 or saline for five days. MC-100093 reduced ethanol consumption in both male and female P rats from Day 1–5. Additionally, MC-100093 upregulated GLT-1 and xCT expression in the mPFC and NAc subregions as compared to ethanol-saline groups in female and male rats. Chronic ethanol intake reduced GLT-1 and xCT expression in the IL and PL in female and male rats, except there was no reduction in GLT-1 expression in the mPFC-PL in female rats. Although, MC-100093 upregulated GLT-1 and xCT expression in the subregions of NAc, we did not observe any reduction in GLT-1 and xCT expression with chronic ethanol intake in female rats. These findings strongly suggest that MC-100093 treatment effectively reduced ethanol intake and upregulated GLT-1 and xCT expression in the mPFC and NAc subregions in male and female P rats.

Region-specific activation in the accumbens nucleus by itch with modified scratch efficacy in mice – a model-free multivariate analysis

Itch is a protective/defensive function with divalent motivational drives. Itch itself elicits an unpleasant experience, which triggers the urge to scratch, relieving the itchiness. Still, it can also result in dissatisfaction when the scratch is too intense and painful or unsatisfactory due to insufficient scratch effect. Therefore, it is likely that the balance between the unpleasantness/pleasure and satisfaction/unsatisfaction associated with itch sensation and scratching behavior is determined by complex brain mechanisms. The physiological/pathological mechanisms underlying this balance remain largely elusive. To address this issue, we targeted the "reward center" of the brain, the nucleus accumbens (NAc), in which itch-responsive neurons have been found in rodents. We examined how neurons in the NAc are activated or suppressed during histamine-induced scratching behaviors in mice. The mice received an intradermal injection of histamine or saline at the neck, and the scratching number was analyzed by recording the movement of the bilateral hind limbs for about 45 min after injection. To experimentally manipulate the scratch efficacy in these histamine models, we compared histamine's behavioral and neuronal effects between mice with intact and clipped nails on the hind paws. As expected, the clipping of the hind limb nail increased the number of scratches after the histamine injection. In the brains of mice exhibiting scratching behaviors, we analyzed the expression of the c-fos gene (Fos) as a readout of an immediate activation of neurons during itch/scratch and dopamine receptors (Drd1 and Drd2) using multiplex single-molecule fluorescence in situ hybridization (RNAscope) in the NAc and surrounding structures. We performed a model-free analysis of gene expression in geometrically divided NAc subregions without assuming the conventional core–shell divisions. The results indicated that even within the NAc, multiple subregions responded differentially to various itch/scratch conditions. We also found different clusters with neurons showing similar or opposite changes in Fos expression and the correlation between scratch number and Fos expression in different itch/scratch conditions. These regional differences and clusters would provide a basis for the complex role of the NAc and surrounding structures in encoding the outcomes of scratching behavior and itchy sensations.

Kappa-opioid receptor stimulation in the nucleus accumbens shell and ethanol drinking: Differential effects by rostro-caudal location and level of drinking

Although the kappa-opioid receptor (KOR) and its endogenous ligand, dynorphin, are believed to be involved in ethanol drinking, evidence on the direction of their effects has been mixed. The nucleus accumbens (NAc) shell densely expresses KORs, but previous studies have not found KOR activation to influence ethanol drinking. Using microinjections into the NAc shell of male and female Long-Evans rats that drank under the intermittent-access procedure, we found that the KOR agonist, U50,488, had no effect on ethanol drinking when injected into the middle NAc shell, but that it promoted intake in males and high-drinking females in the caudal NAc shell and high-drinking females in the rostral shell, and decreased intake in males and low-drinking females in the rostral shell. Conversely, injection of the KOR antagonist, nor-binaltorphimine, stimulated ethanol drinking in low-drinking females when injected into the rostral NAc shell and decreased drinking in high-drinking females when injected into the caudal NAc shell. These effects of KOR activity were substance-specific, as U50,488 did not affect sucrose intake. Using quantitative real-time PCR, we found that baseline gene expression of the KOR was higher in the rostral compared to caudal NAc shell, but that this was upregulated in the rostral shell with a history of ethanol drinking. Our findings have important clinical implications, demonstrating that KOR stimulation in the NAc shell can affect ethanol drinking, but that this depends on NAc subregion, subject sex, and ethanol intake level, and suggesting that this may be due to differences in KOR expression.

Waiting impulsivity in progressive supranuclear palsy-Richardson's syndrome.

Waiting impulsivity in progressive supranuclear palsy-Richardson's syndrome (PSP-RS) is difficult to assess, and its regulation is known to involve nucleus accumbens (NAc) subregions. We investigated waiting impulsivity using the "jumping the gun" (JTG) sign, which is defined as premature initiation of clapping before the start signal in the three-clap test and compared clinical features of PSP-RS patients with and without the sign and analyzed neural connectivity and microstructural changes in NAc subregions. A positive JTG sign was defined as the participant starting to clap before the start sign in the three-clap test. We classified participants into the JTG positive (JTG +) and JTG negative (JTG-) groups and compared their clinical features, microstructural changes, and connectivity between NAc subregions using diffusion tension imaging. The NAc was parcellated into core and shell subregions using data-driven connectivity-based methods. Seventy-seven patients with PSP-RS were recruited, and the JTG + group had worse frontal lobe battery (FAB) scores, more frequent falls, and more occurrence of the applause sign than the JTG- group. A logistic regression analysis revealed that FAB scores were associated with a positive JTG sign. The mean fiber density between the right NAc core and right medial orbitofrontal gyrus was higher in the JTG + group than the JTG- group. We show that the JTG sign is a surrogate marker of waiting impulsivity in PSP-RS patients. Our findings enrich the current literature by deepening our understanding of waiting impulsivity in PSP patients and introducing a novel method for its evaluation.

Accumbens connectivity during deep-brain stimulation differentiates loss of control from physiologic behavioral states

BackgroundLoss of control (LOC) eating, the subjective sense that one cannot control what or how much one eats, characterizes binge-eating behaviors pervasive in obesity and related eating disorders. Closed-loop deep-brain stimulation (DBS) for binge eating should predict LOC and trigger an appropriately timed intervention. Objective/hypothesisThis study aimed to identify a sensitive and specific biomarker to detect LOC onset for DBS. We hypothesized that changes in phase-locking value (PLV) predict the onset of LOC-associated cravings and distinguish them from potential confounding states. MethodsUsing DBS data recorded from the nucleus accumbens (NAc) of two patients with binge eating disorder (BED) and severe obesity, we compared PLV between inter- and intra-hemispheric NAc subregions for three behavioral conditions: craving (associated with LOC eating), hunger (not associated with LOC), and sleep. ResultsIn both patients, PLV in the high gamma frequency band was significantly higher for craving compared to sleep and significantly higher for hunger compared to craving. Maximum likelihood classifiers achieved accuracies above 88% when differentiating between the three conditions. ConclusionsHigh-frequency inter- and intra-hemispheric PLV in the NAc is a promising biomarker for closed-loop DBS that differentiates LOC-associated cravings from physiologic states such as hunger and sleep. Future trials should assess PLV as a LOC biomarker across a larger cohort and a wider patient population transdiagnostically.

The role of functional and structural properties of the nucleus accumbens subregions in eating behavior regulation of bulimia nervosa.

Although studies have demonstrated the involvement of the nucleus accumbens (NAc) in the neurobiology of eating disorders, its alterations in bulimia nervosa (BN) remain largely unknown. This study investigated the structural and functional properties of NAc in patients with BN. Based on the resting-state functional MRI and high-resolution anatomical T1-weighted imaging data acquired from 43 right-handed BN patients and 40 sex-, age- and education-matched right-handed healthy controls (HCs), the group differences in gray matter volume (GMV) and fractional amplitude of low-frequency fluctuation (fALFF) in slow-4 and -5 bands and functional connectivity (FC) of NAc subregions (core and shell) were compared. The relationships between MRI and clinical data were explored in the BN group. Compared with HCs, BN patients showed preserved GMV, decreased fALFF in slow-5 band of the left NAc core and shell, decreased FC between left NAc core and right caudate, and increased FC between all NAc subregions and frontal regions, between all NAc subregions (except the right NAc core) and the supramarginal gyrus (SMG), and between right NAc shell and left middle temporal gyrus. FC between the NAc and SMG was correlated with emotional eating behaviors. Our study revealed preserved GMV, local neuronal activity reduction and functional network reorganization of the NAc in BN. The functional network reorganization of the NAc mainly occurred in the frontal cortex and was correlated with emotional eating behavior. These findings may provide novel insights into the BN using NAc as an entry point. Although studies have demonstrated the involvement of the nucleus accumbens (NAc) in the neurobiology of eating disorders, its alterations in bulimia nervosa (BN) remain largely unknown. We used a multimodal MRI technique to systematically investigate structural and functional alterations in NAc subregions of BN patients and explored the associations between such alterations and maladaptive eating behaviors, hoping to provide novel insights into BN.

Exogenous oxytocin microinjection into the nucleus accumbens shell attenuates social dominance in group-housed male mice

The nucleus accumbens (NAc), a part of the brain's limbic system, is involved in a variety of brain functions, including reward motivation and social hierarchy. Here, the study investigated the effect of intra-NAc different subregions microinjections of oxytocin on social hierarchy regulation. The hierarchical ranking of group-housed male mice in laboratory settings was determined through the tube test, and a new reliable and robust behavior assay—the mate competition test—was proposed. The mice were randomly divided into two groups, and the bilateral guide cannula was implanted into the shell and core of the NAc, respectively. After social dominance stabilized, changes in social hierarchy were determined through the tube test, warm spot, and mate competition tests. Intra-NAc shell microinjections of oxytocin (0.5 μg/site), but not the core (0.5 μg/site), significantly reduced the social dominance of mice. In addition, oxytocin microinjection into both the shell and core of the NAc significantly increased locomotor ability without affecting anxious behaviors. These findings are tremendously important in understanding the functions of the NAc subregions for social dominance and are more likely to indicate the potential of an oxytocin therapeutic strategy for psychiatric disorders and social impairments.

Distinct reward processing by subregions of the nucleus accumbens.

The nucleus accumbens (NAc) plays an important role in motivation and reward processing. Recent studies suggest that different NAc subnuclei differentially contribute to reward-related behaviors. However, how reward is encoded in individual NAc neurons remains unclear. Using invivo single-cell resolution calcium imaging, we find diverse patterns of reward encoding in the medial and lateral shell subdivision of the NAc (NAcMed and NAcLat, respectively). Reward consumption increases NAcLat activity but decreases NAcMed activity, albeit with high variability among neurons. The heterogeneity in reward encoding could be attributed to differences in their synaptic inputs and transcriptional profiles. Specific optogenetic activation of Nts-positive neurons in the NAcLat promotes positive reinforcement, while activation of Cartpt-positive neurons in the NAcMed induces behavior aversion. Collectively, our study shows the organizational and transcriptional differences in NAc subregions and provides a framework for future dissection of NAc subregions in physiological and pathological conditions.

Altered functional connectivity of nucleus accumbens subregions associates with non-motor symptoms in Parkinson's disease.

This study aimed to identify the functional connectivity (FC) changes of nucleus accumbens (NAc) subregions and characterize the association of network changes and non-motor symptoms (NMS) in Parkinson's disease (PD). We enrolled 129 PD patients and 106 healthy controls from our center and the PPMI (Parkinson's Progression Markers Initiative) database. The FC of the bilateral core and shell of the NAc were measured and compared between the two groups. We further used partial least squares correlation to reveal the relationships between altered FC of NAc subregions and manifestations of NMS of PD. The subregions of left core, left shell, and right core had reduced FC with extensive brain regions in PD patients compared with healthy controls. These three subregions were commonly associated with depression, anxiety, apathy, and cognitive impairment. Moreover, the left core and left shell were associated with excessive daytime sleepiness, whereas the right core was associated with olfactory impairment and rapid eye movement sleep behavior disorder. This study for the first time identified the neural network changes of NAc subregions in PD and the associations between network changes and phenotypes of NMS. Our findings provide new insights into the pathogenesis of NMS in PD.

The incubation of cocaine craving is dissociated from changes in glial cell markers within prefrontal cortex and nucleus accumbens of rats

• Extended-access cocaine self-administration elicits an incubation of cocaine-seeking behavior during protracted withdrawal. • Extended-access cocaine self-administration lowers ventromedial prefrontal cortex expression of several glial cell markers in early withdrawal that persist into protracted withdrawal. • Extended-access cocaine self-administration produces few effects upon the expression of glial cell markers in the dorsomedial prefrontal cortex, or nucleus accumbens subregions. The majority of neurobiological research on cocaine addiction has centered on neuronal pathology, ignoring the fact that glial cells are critical contributors to brain function. The present study examined the expression of various glial cell subtype-specific proteins within forebrain regions that exhibit functional anomalies in addiction. For this, immunoblotting was conducted for a variety of markers of astrocytes and oligodendrocytes within prefrontal cortex (PFC) and nucleus accumbens (NAC) subregions of cocaine-abstinent rats (3 or 30 days). Cocaine-experienced rats exhibited a time-dependent increase in cocaine craving. Within ventral PFC, cocaine-experienced rats exhibited reduced expression of myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and the NG2(+) proteoglycan that persisted into protracted withdrawal. Within the NAC core, a persistent reduction in Cx43 expression was also observed. No statistically significant protein changes were observed for the dPFC or the NAC shell. Thus, although a history of extended cocaine-access induced an incubation of cocaine craving, the observed changes in our glial-specific markers were time-independent during withdrawal. These data from rat are consistent with imagining and post-mortem findings from humans, indicating perturbations in oligodendrocyte function in those with cocaine use disorder. As myelin is critical for normal neuronal functioning and survival, the present data suggest a reduction in the functional integrity of oligodendrocytes as a potential mechanism underpinning the enduring PFC hypofunction reported in cocaine use disorder.

Mesoaccumbal Dopamine Heterogeneity: What Do Dopamine Firing and Release Have to Do with It?

Ventral tegmental area (VTA) dopamine (DA) neurons are often thought to uniformly encode reward prediction errors. Conversely, DA release in the nucleus accumbens (NAc), the prominent projection target of these neurons, has been implicated in reinforcement learning, motivation, aversion, and incentive salience. This contrast between heterogeneous functions of DA release versus a homogeneous role for DA neuron activity raises numerous questions regarding how VTA DA activity translates into NAc DA release. Further complicating this issue is increasing evidence that distinct VTA DA projections into defined NAc subregions mediate diverse behavioral functions. Here, we evaluate evidence for heterogeneity within the mesoaccumbal DA system and argue that frameworks of DA function must incorporate the precise topographic organization of VTA DA neurons to clarify their contribution to health and disease.

Immunolabeling Provides Evidence for Subregions in the Songbird Nucleus Accumbens and Suggests a Context-Dependent Role in Song in Male European Starlings (Sturnus vulgaris)

Birdsong is well known for its role in mate attraction during the breeding season. However, many birds, including European starlings (Sturnus vulgaris), also sing outside the breeding season as part of large flocks. Song in a breeding context can be extrinsically rewarded by mate attraction; however, song in nonbreeding flocks, referred to here as gregarious song, results in no obvious extrinsic reward and is proposed to be intrinsically rewarded. The nucleus accumbens (NAC) is a brain region well known to mediate reward and motivation, which suggests it is an ideal candidate to regulate reward associated with gregarious song. The goal of this study was to provide new histochemical information on the songbird NAC and its subregions (rostral pole, core, and shell) and to begin to determine subregion-specific contributions to gregarious song in male starlings. We examined immunolabeling for tyrosine hydroxylase (TH), neurotensin, and enkephalin (ENK) in the NAC. We then examined the extent to which gregarious and sexually motivated song differentially correlated with immunolabeling for the immediate early genes FOS and ZENK in each subdivision of the NAC. We found that TH and ENK labeling within subregions of the starling NAC was generally similar to patterns seen in the core and shell of NACs in mammals and birds. Additionally, we found that gregarious song, but not sexually motivated song, positively correlated with FOS in all NAC subregions. Our observations provide further evidence for distinct subregions within the songbird NAC and suggest the NAC may play an important role in regulating gregarious song in songbirds.

Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats.

Δ9-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and is responsible for cannabis-related neuropsychiatric side effects, including abnormal affective processing, cognitive and sensory filtering deficits and memory impairments. A critical neural region linked to the psychotropic effects of THC is the nucleus accumbens shell (NASh), an integrative mesocorticolimbic structure that sends and receives inputs from multiple brain areas known to be dysregulated in various disorders, including schizophrenia and anxiety-related disorders. Considerable evidence demonstrates functional differences between posterior vs. anterior NASh sub-regions in the processing of affective and cognitive behaviours influenced by THC. Nevertheless, the neuroanatomical regions and local molecular pathways responsible for these psychotropic effects are not currently understood. The objectives of this study were to characterize the effects of intra-accumbens THC in the anterior vs. posterior regions of the NASh during emotional memory formation, sensorimotor gating and anxiety-related behaviours. We performed an integrative series of translational behavioural pharmacological studies examining anxiety, sensorimotor gating and fear-related associative memory formation combined with regionally specific molecular signalling analyses in male Sprague Dawley rats. We report that THC in the posterior NASh causes distortions in emotional salience attribution, impaired sensory filtering and memory retention and heightened anxiety, through a glycogen-synthase-kinase-3 (GSK-3)-β-catenin dependent signalling pathway. In contrast, THC in the anterior NASh produces anxiolytic effects via modulation of protein kinase B (Akt) phosphorylation states. These findings reveal critical new insights into the neuroanatomical and molecular mechanisms associated with the differential neuropsychiatric side effects of THC in dissociable nucleus accumbens sub-regions.

Nucleus accumbens dichotomically controls social dominance in male mice.

Social dominance versus social submissiveness is a basic behavioral trait of social animals such as human beings and laboratory mice. The brain regions associated with this behavior have been intensely investigated, and early neuroimaging research on human subjects implies that the nucleus accumbens (NAc) might be involved in encoding social dominance. However, the underlying circuitry and synaptic mechanism are largely unknown. In this study, by introducing lesions to both NAc subregions, the shell and core, a causal relationship is established between social dominance and both NAc subregions. A further electrophysiology investigation on the circuitry of these two subregions revealed that the postsynaptic strength of excitatory synapses onto the medium spiny neurons that express the D1 dopamine receptors in the shell is negatively correlated, and the postsynaptic strength of excitatory synapses onto the medium spiny neurons that express the D2 dopamine receptors in the core is positively correlated, with social dominance. Correspondingly, a DREADD investigation revealed that the activities of these respective medium spiny neurons suppress and promote social dominance. These findings identify a neural substrate for social dominance, implying the potential for a therapeutic strategy for treating related psychiatric disorders.

Dissociable roles of the nucleus accumbens core and shell subregions in the expression and extinction of conditioned fear

The nucleus accumbens (NAc), consisting of core (NAcC) and shell (NAcS) sub-regions, has primarily been studied as a locus mediating the effects of drug reward and addiction. However, there is ample evidence that this region is also involved in regulating aversive responses, but the exact role of the NAc and its subregions in regulating associative fear processing remains unclear. Here, we investigated the specific contribution of the NAcC and NAcS in regulating both fear expression and fear extinction in C57BL/6J mice. Using Arc expression as an indicator of neuronal activity, we first show that the NAcC is specifically active only in response to an associative fear cue during an expression test. In contrast, the NAcS is specifically active during fear extinction. We next inactivated each subregion using lidocaine and demonstrated that the NAcC is necessary for fear expression, but not for extinction learning or consolidation of extinction. In contrast, we demonstrate that the NAcS is necessary for the consolidation of extinction, but not fear expression or extinction learning. Further, inactivation of mGluR1 or ERK signaling specifically in the NAcS disrupted the consolidation of extinction but had no effect on fear expression or extinction learning itself. Our data provide the first evidence for the importance of the ERK/MAPK pathway as the underlying neural mechanism facilitating extinction consolidation within the NAcS. These findings suggest that the NAc subregions play dissociable roles in regulating fear recall and the consolidation of fear extinction, and potentially implicate them as critical regions within the canonical fear circuit.

CB1R activation in nucleus accumbens core promotes stress-induced reinstatement of cocaine seeking by elevating extracellular glutamate in a drug-paired context

Preclinical models of stress-induced relapse to drug use have shown that the dysregulation of glutamatergic transmission within the nucleus accumbens (NA) contributes notably to the reinstatement of cocaine-seeking behavior in rodents. In this sense, there has been increasing interest in the cannabinoid type-1 receptor (CB1R), due to its crucial role in modulating glutamatergic neurotransmission within brain areas involved in drug-related behaviors. This study explored the involvement of CB1R within the NA subregions in the restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP), as well as in the regulation of glutamatergic transmission, by using a pharmacological approach and the in vivo microdialysis sampling technique in freely moving rats. CB1R blockade by the antagonist/inverse agonist AM251 (5 nmol/0.5 μl/side) or CB1R activation by the agonist ACEA (0.01 fmol/0.5 μl/side), prevented or potentiated restraint stress-induced reinstatement of cocaine-CPP, respectively, after local administration into NAcore, but not NAshell. In addition, microdialysis experiments demonstrated that restraint stress elicited a significant increase in extracellular glutamate in NAcore under reinstatement conditions, with the local administration of AM251 or ACEA inhibiting or potentiating this, respectively. Interestingly, this rise specifically corresponded to the cocaine-associated CPP compartment. We also showed that this context-dependent change in glutamate paralleled the expression of cocaine-CPP, and disappeared after the extinction of this response. Taken together, these findings demonstrated the key role played by CB1R in mediating reinstatement of cocaine-CPP after restraint stress, through modulation of the context-specific glutamate release within NAcore. Additionally, CB1R regulation of basal extracellular glutamate was demonstrated and proposed as the underlying mechanism.

Dopamine release and its control over early Pavlovian learning differs between the NAc core and medial NAc shell

Dopamine neurons respond to cues to reflect the value of associated outcomes. These cue-evoked dopamine responses can encode the relative rate of reward in rats with extensive Pavlovian training. Specifically, a cue that always follows the previous reward by a short delay (high reward rate) evokes a larger dopamine response in the nucleus accumbens (NAc) core relative to a distinct cue that always follows the prior reward by a long delay (low reward rate). However, it was unclear if these reward rate dopamine signals are evident during early Pavlovian training sessions and across NAc subregions. To address this, we performed fast-scan cyclic voltammetry recordings of dopamine levels to track the pattern of cue- and reward-evoked dopamine signals in the NAc core and medial NAc shell. We identified regional differences in the progression of cue-evoked dopamine signals across training. However, the dopamine response to cues did not reflect the reward rate in either the NAc core or the medial NAc shell during early training sessions. Pharmacological experiments found that dopamine-sensitive conditioned responding emerged in the NAc core before the medial NAc shell. Together, these findings illustrate regional differences in NAc dopamine release and its control over behavior during early Pavlovian learning.