Accumbens Research Articles

Enhancing chronic low back pain management: an initial neuroimaging study of a mobile interoceptive attention training.

Chronic low back pain (cLBP) poses significant challenges, often addressed through avoidance or distraction. Emerging evidence suggests that mind-body interventions, like our novel Mind Your Pain (MyP) smartphone mobile application, may offer relief. We conducted a single-arm, mixed-methods neuroimaging study to assess the degree to which treatment response to our 8-week intervention, as measured by the reduction in the Pain, Enjoyment of Life and General Activity Scale (PEG), was associated with enhanced pain-related insula activation over time. Twenty-nine individuals with cLBP completed patient-reported assessments, qualitative sensory testing (QST) measures, and neuroimaging pre- and post-MyP. Functional MRI data during experimental heat pain on the left forearm were collected and analyzed, comparing responders (≥50% reduction in PEG scores) and non-responders. MyP led to significant decreases in PEG scores overall. Furthermore, MyP responders exhibited increased pain-related activation in key brain regions, including the contralateral posterior insula, bilateral ventral anterior insula, ventral anterior cingulate, dorsolateral prefrontal cortex, and nucleus accumbens. Although baseline behavioral and sensory measures did not differ between the two responder groups, baseline neural differences related to the impact of the endogenous back pain were observed. MyP appears to modify pain response and underlying neural circuitry, suggesting neural changes in interoception may serve as biomarkers for mind-body interventions in cLBP. This study highlights the potential of MyP as a novel approach for cLBP management, warranting further investigation.

The Influence of Strain and Sex on High Fat Diet-Associated Alterations of Dopamine Neurochemistry in Mice.

Objective: The objective of this study was to determine the influence of sex and strain on striatal and nucleus accumbens dopamine neurochemistry and dopamine-related behavior due to a high-saturated-fat diet (HFD). Methods: Male and female C57B6/J (B6J) and Balb/cJ (Balb/c) mice were randomly assigned to a control-fat diet (CFD) containing 10% kcal fat/g or a mineral-matched HFD containing 60% kcal fat/g for 12 weeks. Results: Intraperitoneal glucose tolerance testing (IPGTT) and elevated plus maze experiments (EPM) confirmed that an HFD produced marked blunting of glucose clearance and increased anxiety-like behavior, respectively, in male and female B6J mice. Electrically evoked dopamine release in the striatum and reuptake in the nucleus accumbens (NAc), as measured by ex vivo fast scan cyclic voltammetry, was reduced for HFD-fed B6J females. Impairment in glucose metabolism explained HFD-induced changes in dopamine neurochemistry for B6J males and, to a lesser extent, Balb/c males. The relative expressions of protein markers associated with the activation of microglia, ionized calcium binding adaptor molecule (Iba1) and cluster of differentiation molecule 11b (CD11b) in the striatum were increased due to an HFD for B6J males but were unchanged or decreased amongst HFD-fed Balb/c mice. Conclusions: Our findings demonstrate that strain and sex influence the insulin- and microglia-dependent mechanisms of alterations to dopamine neurochemistry and associated behavior due to an HFD.

Altered structure and functional connection of subcortical gray matter in female patients with classical trigeminal neuralgia.

The etiology of classical trigeminal neuralgia (CTN) is still unclear. A better understanding of the cerebral structural and functional changes in female patients with CTN may provide important novel insights into the pathophysiologic mechanisms of female CTN. A total 37 female CTN patients were included and referred to MRI scans, comprising with 19 left CTN and 18 right CTN patients. We analyzed the volume and shape of subcortical gray matter (GM), and the functional connectivity (FC) between the accumbens nucleus (NAc) and whole brain in right and left CTN patients respectively. We found left CTN patients had a reduced right NAc volume compared to controls, similarly, the right CTN had the decreased volume in the left NAc. Vertex-wise shapes of right NAc in left CTN patients showed significant regional shape deformation on the anterior, medial and ventroposterior aspects, in contrast, left NAc of right CTN patients showed significant regional shape deformation on the anterior and posterior aspect. Furthermore, patients with left CTN showed significantly lower FC between the right NAc and right orbitofrontal cortex than control subjects. The volume of NAc in all CTN was significantly related to the perception of present pain intensity. The CTN might be majorly caused by volume reduction in NAc. A greater understanding of the neurobiological basis of pain-related changes in NAc will provide the knowledge for the development of novel NAc based therapeutic targets for pain management or even prevention in CTN patients.

Dopamine-mediated formation of a memory module in the nucleus accumbens for goal-directed navigation.

Spatial memories guide navigation efficiently toward desired destinations. However, the neuronal and circuit mechanisms underlying the encoding of goal locations and its translation into goal-directed navigation remain unclear. Here we demonstrate that mice rapidly form a spatial memory of a shelter during shelter experiences, guiding escape behavior toward the goal location-a shelter-when under threat. Dopaminergic neurons in the ventral tegmental area and their projection to the nucleus accumbens (NAc) encode safety signals associated with the shelter. Optogenetically induced phasic dopamine signals are sufficient to create a place memory that directs escape navigation. Converging dopaminergic and hippocampal glutamatergic inputs to the NAc mediate the formation of a goal-related memory within a subpopulation of NAc neurons during shelter experiences. Artificial co-activation of this goal-related NAc ensemble with neurons in the dorsal periaqueductal gray was sufficient to trigger memory-guided, rather than random, escape behavior. These findings provide causal evidence of cognitive circuit modules linking memory with goal-directed action.

Shank3 deficiency alters midbrain GABAergic neuron morphology, GABAergic markers and synaptic activity in primary striatal neurons

Abnormalities in gamma-aminobutyric acid (GABA)ergic neurotransmission play a role in the pathogenesis of autism, although the mechanisms responsible for alterations in specific brain regions remain unclear. Deficits in social motivation and interactions are core symptoms of autism, likely due to defects in dopaminergic neural pathways. Therefore, investigating the morphology and functional roles of GABAergic neurons within dopaminergic projection areas could elucidate the underlying etiology of autism. The aim of this study was to (1) compare the morphology and arborization of glutamate decarboxylase (GAD)-positive neurons from the midbrain tegmentum; (2) evaluate synaptic activity in primary neurons from the striatum; and (3) assess GABAergic postsynaptic puncta in the ventral striatum of wild-type (WT) and Shank3-deficient mice. We found a significant decrease in the number of short neurites in GAD positive primary neurons from the midbrain tegmentum in Shank3-deficient mice. The application of a specific blocker of GABAA receptors (GABAAR) revealed significantly increased frequency of spontaneous postsynaptic currents (sPSCs) in Shank3-deficient striatal neurons compared to their WT counterparts. The mean absolute amplitude of the events was significantly higher in striatal neurons from Shank3-deficient compared to WT mice. We also observed a significant reduction in gephyrin/GABAAR γ2 colocalization in the striatum of adult male Shank3-deficient mice. The gene expression of collybistin was significantly lower in the nucleus accumbens while gephyrin and GABAAR γ2 were lower in the ventral tegmental area (VTA) in male Shank3-deficient compared to WT mice. In conclusion, Shank3 deficiency leads to alterations in GABAergic neurons and impaired GABAergic function in dopaminergic brain areas. These changes may underlie autistic symptoms, and potential interventions modulating GABAergic activity in dopaminergic pathways may represent new treatment modality.

The Role of Motivation in Decision-Making and Underlying Neural Mechanism

This paper presents crucial findings on how motivation, both internal and external, significantly influences decision-making processes at cognitive and neural levels. It highlights the role of reward anticipation and uncertainty in shaping decision-making behavior, particularly focusing on brain regions like the prefrontal cortex, amygdala, and dopaminergic pathways, which govern strategic and risk-related decisions. Studies involving psychiatric conditions, such as schizophrenia, and healthy individuals using fMRI reveal that increased motivation enhances decision-making strategies by activating frontal and parietal brain regions, while certain areas like the Orbitofrontal Cortex (OFC) show less involvement. Additionally, the essay explores the role of insight-driven internal motivation, showing that moments of sudden clarity (AHA! experiences) can elevate risk-taking behavior by stimulating the nucleus accumbens (NAcc), a key region involved in reward processing. The research also delves into strategic decision-making theories, emphasizing the balance between logical reasoning and instinctive, politically influenced decision-making processes within organizations. The essay concludes by underscoring the need for further research into the neural mechanisms linking motivation and decision-making, particularly the impact of neurotransmitter systems and individual differences in neural responsiveness to rewards. This deeper understanding could lead to enhanced strategies for improving decision-making outcomes across various fields, including healthcare, management, and personal decision-making, offering insights into the complex interplay between motivation, cognition, and neural activity.

Incentive motivation for palatable food blocked by intra-accumbens melanin-concentrating hormone (MCH) receptor-1 antagonist in female rats

Melanin-concentrating hormone (MCH) activity in the nucleus accumbens (Acb) has been shown to influence feeding behavior, yet this has not been characterized in terms of homeostatic vs. hedonic feeding processes. Hedonic feeding, driven by palatability rather than energy deficit, can be modeled through intra-Acb administration of the selective μ-opioid receptor agonist d-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), which preferentially increases consumption and incentive motivation to obtain preferred palatable food. Pharmacological activation of MCH 1 receptors (MCHR1) within Acb has been shown to promote general feeding of chow in males, but not females. However, the effects of MCH on the incentive motivation to obtain preferred palatable food have not been explored. Here, we investigated the role of MCHR1 within the Acb in DAMGO-induced incentive motivation to obtain a sucrose pellet reward. Female Sprague Dawley rats were trained and tested for operant responding under a progressive ratio (PR) breakpoint in response to concurrent intra-Acb administration of DAMGO (0 μg and 0.025 μg/.5 μl/side) immediately following intra-Acb administration of the MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/.5 μl/side), in a counterbalanced fashion. As expected, DAMGO significantly increased PR breakpoint and overall active lever presses. SNAP-94847 did not influence PR breakpoint by itself, compared to vehicle; however, both 1.5 and 15 μg doses of SNAP-94847 significantly blocked the increased PR breakpoint produced by intra-Acb DAMGO. The results of the study demonstrate that Acb MCHR1 may play a specific role in the hedonically-driven motivation for palatable food in females.

Functional connectivity between the nucleus accumbens and amygdala underlies avoidance learning during adolescence: Implications for developmental psychopathology.

Reward and threat processes work together to support adaptive learning during development. Adolescence is associated with increasing approach behavior (e.g., novelty-seeking, risk-taking) but often also coincides with emerging internalizing symptoms, which are characterized by heightened avoidance behavior. Peaking engagement of the nucleus accumbens (NAcc) during adolescence, often studied in reward paradigms, may also relate to threat mechanisms of adolescent psychopathology. 47 typically developing adolescents (9.9-22.9 years) completed an aversive learning task during functional magnetic resonance imaging, wherein visual cues were paired with an aversive sound or no sound. Task blocks involved an escapable aversively reinforced stimulus (CS+r), the same stimulus without reinforcement (CS+nr), or a stimulus that was never reinforced (CS-). Parent-reported internalizing symptoms were measured using Revised Child Anxiety and Depression Scales. Functional connectivity between the NAcc and amygdala differentiated the stimuli, such that connectivity increased for the CS+r (p = .023) but not for the CS+nr and CS-. Adolescents with greater internalizing symptoms demonstrated greater positive functional connectivity for the CS- (p = .041). Adolescents show heightened NAcc-amygdala functional connectivity during escape from threat. Higher anxiety and depression symptoms are associated with elevated NAcc-amygdala connectivity during safety, which may reflect poor safety versus threat discrimination.

Estrogenic control of reward prediction errors and reinforcement learning.

Gonadal hormones act throughout the brain 1 , and neuropsychiatric disorders vary in symptom severity over the reproductive cycle, pregnancy, and perimenopause 2-4 . Yet how hormones influence cognitive processes is unclear. Exogenous 17 β -estradiol modulates dopamine signaling in the nucleus accumbens core (NAcc) 5,6 , which instantiates reward prediction errors (RPEs) for reinforcement learning 7-16 . Here we show that endogenous 17 β -estradiol enhances RPEs and sensitivity to previous rewards by reducing dopamine reuptake proteins in the NAcc. Rats performed a task with different reward states; they adjusted how quickly they initiated trials across states, balancing effort against expected rewards. NAcc dopamine reflected RPEs that predicted and causally influenced initiation times. Elevated endogenous 17 β -estradiol increased sensitivity to reward states by enhancing dopaminergic RPEs in the NAcc. Proteomics revealed reduced dopamine transporter expression. Finally, knockdown of midbrain estrogen receptors suppressed reinforcement learning. 17 β -estradiol therefore controls RPEs via dopamine reuptake, mechanistically revealing how hormones influence neural dynamics for motivation and learning.

Sex-specific Concordance of Striatal Transcriptional Signatures of Opioid Addiction in Human and Rodent Brains.

Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current, frontline addiction treatment strategies fail to produce lasting abstinence in most users. This underscores the lasting effects of chronic opioid exposure and emphasizes the need to understand the molecular mechanisms of drug seeking and taking, but also how those alterations persist through acute and protracted withdrawal. Here, we used RNA sequencing in post-mortem human tissue from males (n=10) and females (n=10) with OUD and age and sex-matched comparison subjects. We compared molecular alterations in the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC) between humans with OUD and rodent models across distinct stages of opioid use and withdrawal (acute and prolonged) using differential gene expression and network-based approaches. We found that the molecular signature in the NAc of females with OUD mirrored effects seen in the NAc of female mice at all stages of exposure. Conversely, males with OUD showed strong overlap in expression profile with rats in acute withdrawal. Co-expression networks involved in post-transcriptional modification of RNA and epigenetic modification of chromatin state. This study provides fundamental insight into the converging molecular pathways altered by opioids across species. Further, this work helps to disentangle which alterations observed in humans with OUD are driven by acute drug exposure and which alterations are consequences of chronic exposure.

Possible association of elevated CSF IL-6 levels with anxiety and frustration in psychiatric disorders.

Neuroinflammation is an important causal factor for a variety of psychiatric disorders. We previously reported increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and major depressive disorder. The present study aimed to examine the possible association of interleukin-6 levels with anxiety and frustration, negative valence symptoms shared in various psychiatric disorders. We included 129 patients with psychiatric disorders and 70 controls. CSF and plasma interleukin-6 levels were measured by immunoassay kits, and psychological symptoms were assessed with the State-Trait Anxiety Inventory, and the Basic Psychological Need Satisfaction and Frustration Scale. To examine regional cerebral blood flow, patients underwent arterial spin labeling analysis using magnetic resonance imaging. Cerebrospinal fluid interleukin-6 levels were significantly correlated with State-Trait Anxiety Inventory-trait anxiety (r = 0.25, P = 0.046) and Basic Psychological Need Satisfaction and Frustration Scale-autonomy frustration scores (r = 0.29, P = 0.018). Patients with abnormally high cerebrospinal fluid interleukin-6 levels (defined >97.5 percentile of the controls) had higher scores for trait anxiety (P = 0.035) and autonomy frustration (P = 0.026), and significantly increased regional cerebral blood flow in the left superior temporal gyrus, bilateral nucleus accumbens, and cerebellum than the remaining patients. Patients with elevated cerebrospinal fluid interleukin-6 constitute a subpopulation of psychiatric disorders associated with anxiety and autonomy frustration, which may be related to altered functions in specific brain areas.

Focused Ultrasound Combined With Microbubbles Attenuate Symptoms in Heroin-Addicted Mice

ObjectiveTo explore the efficacy and mechanisms of stimulating the nucleus accumbens (NAc) in heroin-addicted mice using focused ultrasound and microbubbles (MBs). MethodsThe conditioned place preference (CPP) method was employed to establish a heroin-addicted mice model. Mice were randomized into control (C), heroin (H), heroin + ultrasound (H + U) and H + U + MBs. Ultrasound (2 MHz fundamental frequency, 1.34 MPa peak-negative pressure, 1 MHz pulse repetition frequency, 5% duty cycle, 15 min/d, over 2 d) was applied to stimulate the NAc in the latter 2 groups. Whereas H + U + MBs received an injection of sulfur hexafluoride MBs during the stimulation. Subsequently, CPP scores, open-field test (OFT), and elevated plus-maze test (EPMT) were conducted to assess behavioral changes in addiction memory, anxiety and exercise status. HE staining was performed to detect pathological structures. Neurotransmitters such as dopamine (DA), serotonin (5-HT) and glutamate (Glu) were detected using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Transmission electron microscopy (TEM) was used to observe ultrastructural changes of synapses in NAc. Immunohistochemistry (IHC) was utilized to detect Cleaved Caspase-3 in the NAc region. Western blotting (WB) was used to detect the protein expression of Cleaved Caspase-3, Bax and Bcl-2 in NAc. ResultsHE staining showed small patches of erythrocyte exudation were observed in the NAc and adjacent areas in H + U + MBs. The CPP scores of H + U + MBs were lower (p < 0.05) than H. After ultrasound treatment, all indices of the OFT and EPMT in H + U + MBs were significantly higher than H (p < 0.05). UPLC-MS/MS revealed that the levels of DA, 5-HT and Glu in H + U + MBs were lower than H (p < 0.01). TEM showed decrease the number of synapses (p < 0.05), and noticeable swelling of mitochondria, membrane damage, as well as damage to the cristae. Further detection by IHC and WB showed that the pro-apoptotic proteins Cleaved Caspase-3 and Bax increased and Bcl-2 decreased as anti-apoptotic proteins after ultrasound combined with MBs (p < 0.05). ConclusionFocused ultrasound combined with MBs stimulate the NAc can weaken the addictive memory and improve anxiety of heroin-related mice. The mechanical effect of ultrasound combined with the cavitation effect may be a potential treatment for addiction.

Abstinence from cocaine self-administration promotes microglia pruning of astrocytes which drives cocaine-seeking behavior.

Rodent drug self-administration leads to compromised ability of astrocytes to maintain glutamate homeostasis within the brain's reward circuitry, as well as reductions in surface area, volume, and synaptic colocalization of astrocyte membranes. However, the mechanisms driving astrocyte responses to cocaine are unknown. Here, we report that long-access cocaine self-administration followed by prolonged home cage abstinence results in decreased branching complexity of nucleus accumbens astrocytes, characterized by the loss of peripheral processes. Using a combination of confocal fluorescence microcopy and immuno-gold electron microscopy, we show that alterations in astrocyte structural features are driven by microglia phagocytosis, as labeled astrocyte membranes are found within microglia phagolysosomes. Inhibition of complement C3-mediated phagocytosis using the neutrophil inhibitory peptide (NIF) rescued astrocyte structure and decreased cocaine seeking behavior following cocaine self-administration and abstinence. Collectively, these results provide evidence for microglia pruning of accumbens astrocytes across cocaine abstinence which mediates cocaine craving.

Disrupted functional connectivity of bilateral nucleus accumbens in major depressive disorder with and without melancholic features.

Our study aims to explore the differences in functional connectivity in the nucleus accumbens (NAc) between patients with melancholic depression and non-melancholic depression (NMD) and their relation to melancholic depression's pathogenesis. We recruited 60 melancholic depression, 58 NMD, and 80 healthy controls, all matched for gender, age, and education. Functional connectivity analysis focused on bilateral NAc as the region of interest, comparing it with the whole brain and correlating significant differences with clinical scores. Melancholic depression patients showed reduced functional connectivity between the left NAc and anterior brain regions, and between the right NAc and temporal and frontal areas, compared to healthy controls. In contrast, NMD patients displayed reduced functional connectivity only between the left NAc and the posterior cingulate cortex. Melancholic depression patients also exhibited increased functional connectivity between the right NAc and the middle frontal gyrus, unlike NMD patients. The findings suggest that melancholic depression patients exhibit unique NAc functional connectivity patterns, particularly with the default mode network and prefrontal areas, suggesting atypical reward-circuitry interactions. The right NAc's connection to the prefrontal gyrus may distinguish melancholic depression from NMD.

Opioid drug seeking after early-life adversity: a role for delta opioid receptors

Opioid use disorder (OUD) is associated with a history of early-life adversity (ELA), an association that is particularly strong in women. In a rodent model, we previously found that ELA enhances risk for opioid addiction selectively in females, but the mechanisms for this effect are unclear. Here, we show that ELA robustly alters cFos responses to opioid drugs in females’ nucleus accumbens (NAc) and basolateral amygdala (BLA), but not elsewhere. We further identify delta opioid receptors (DOR), which mature in the first week of life and thus later than kappa or mu opioid receptors, as a potential mediator of ELA's impacts on reward circuit functions. Accordingly, DOR mRNA in NAc was persistently reduced in adult females with ELA history. Moreover, pharmacological stimulation of NAc DORs increased opioid demand in control females (recapitulating the ELA phenotype), while blocking DORs in ELA females conversely reduced high-effort drug consumption, simulating the control rearing phenotype. These findings support a role for NAc DORs in mediating ELA-induced opioid vulnerability. In contrast, BLA neurons expressing DOR protein do not overlap heroin- responsive cells in ELA rats, arguing against a direct relationship of BLA DORs to heroin's addiction-relevant actions in the brain. Together, these results suggest a novel and selective role for NAc DORs in contributing to enduring, ELA-provoked vulnerability to OUD.

Dopamine transmission at D1 and D2 receptors in the nucleus accumbens contributes to the expression of incubation of cocaine craving.

Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or "incubates" during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex or significant interaction of sex with other factors in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.

How life events may confer vulnerability to addiction: the role of epigenetics.

Substance use disorder (SUD) represents a large and growing global health problem. Despite the strong addictive potency of drugs of abuse, only a minority of those exposed develop SUDs. While certain life experiences (e.g., childhood trauma) may increase subsequent vulnerability to SUDs, mechanisms underlying these effects are not yet well understood. Given the chronic and relapsing nature of SUDs, and the length of time that can elapse between prior life events and subsequent drug exposure, changes in SUD vulnerability almost certainly involve long-term epigenetic dysregulation. To validate this idea, functional effects of specific epigenetic modifications in brain regions mediating reinforcement learning (e.g., nucleus accumbens, prefrontal cortex) have been investigated in a variety of animal models of SUDs. In addition, the effects of epigenetic modifications produced by prior life experiences on subsequent SUD vulnerability have been studied, but mostly in a correlational manner. Here, we review how epigenetic mechanisms impact SUD-related behavior in animal models and summarize our understanding of the relationships among life experiences, epigenetic regulation, and future vulnerability to SUDs. Despite variations in study design, epigenetic modifications that most consistently affect SUD-related behavior are those that produce predominantly unidirectional effects on gene regulation, such as DNA methylation and histone phosphorylation. Evidence explicitly linking environmentally induced epigenetic modifications to subsequent SUD-related behavior is surprisingly sparse. We conclude by offering several directions for future research to begin to address this critical research gap.

State- and Circuit-Dependent Opponent Processing of Fear.

The presence of valence coding neurons in the basolateral amygdala (BLA) that form distinct projections to other brain regions implies functional opposition between aversion and reward during learning. However, evidence for opponent interactions in fear learning is sparse and may only be apparent under certain conditions. Here we test this possibility by studying the roles of the BLA→central amygdala (CeA) and BLA→nucleus accumbens (Acb) pathways in fear learning in male rats. First, we assessed the organization of these pathways in the rat brain. BLA→CeA and BLA→Acb pathways were largely segregated in the BLA but shared overlapping molecular profiles. Then we assessed activity of the BLA→CeA and BLA→Acb pathways during two different forms of fear learning-fear learning in a neutral context and fear learning in a reward context. BLA→CeA neurons were robustly recruited by footshock regardless of where fear learning occurred, whereas recruitment of BLA→Acb neurons was state-dependent because footshock only recruited this pathway in a reward context. Finally, we assessed the causal roles of activity in these pathways in fear learning. Photoinhibition of the BLA→CeA pathway during the footshock US impaired fear learning, regardless of where fear learning occurred. In contrast, photoinhibition of the BLA→Acb pathway augmented fear learning, but only in the reward context. Taken together, our findings show circuit- and state-dependent opponent processing of fear. Footshock activity in the BLA→Acb pathway limits how much fear is learned.

Delay discounting and nucleus accumbens functional connectivity are related to weight status in adolescents from the ABCD study.

Despite the growing epidemic of paediatric obesity, questions remain regarding potential neural mechanisms for individual risk. Delay discounting is a cognitive process of comparison of valuation between immediate and delayed reward, which has been inconsistently linked to weight status. Moreover, central to the brain's reward system is the nucleus accumbens, a region structurally and functionally altered in obesity. This study aimed to examine the relationships between two continuous metrics of weight status, performance on a monetary delay-discounting task and nucleus accumbens functional connectivity in 10-12-year-olds from the Adolescent Brain and Cognitive Development (ABCD) Study. Using multilevel longitudinal linear modelling, we found greater discounting was associated with higher BMI Z-scores (BMIz) and waist-to-height ratio Z-scores (WHtRz) (N = 3819). Moreover, we observed functional connectivity of the nucleus accumbens to the cingulo-opercular, dorsal attention, fronto-parietal, salience and ventral attention networks were predictive of BMIz (N = 1817). Nucleus accumbens functional connectivity was not found to mediate the association between delay-discounting behaviour and BMIz. Delay discounting and nucleus accumbens functional connectivity are independently related to weight status in a large sample of early adolescents. A better understanding of the relationship between reward and overeating behaviours may better inform obesity interventions.

Immunomodulatory treatment may change functional and structural brain imaging in severe mental disorders

Neuroinflammation has been implicated in the pathophysiology of schizophrenia and obsessive-compulsive disorder (OCD) and deviations in brain structure and connectivity are seen in these disorders. Here, we explore the effects of a potent immunomodulatory treatment on neuroimaging. In a pilot study of rituximab treatment in schizophrenia and OCD, a subgroup (n = 13) underwent structural and functional magnetic resonance imaging before and 5 months after treatment, to study longitudinal changes in resting-state functional connectivity (rsFC) and voxel-based morphometry (VBM).A hypothesis-free exploratory whole-brain analysis was performed twice to assess changes in rsFC, using anterior cingulate cortex, anterior insula, posterior insula and nucleus accumbens as seed regions. There were significant interactions (diagnosis x time) in connectivity between right posterior insula and two clusters encompassing basal ganglia and anterior frontal pole, and between left anterior insula and a cluster in basal ganglia, where connectivity decreased in OCD and increased in schizophrenia. The increase of connectivity after rituximab, between left anterior insula and parts of cerebellum and lingual gyrus and between left posterior insula and parts of cerebellum, correlated with improved global psychosocial functioning according to the Personal and Social Performance Scale, especially in schizophrenia. VBM analysis identified two clusters with increased grey matter volumes (GMV) after rituximab, one in right insula overlapping one of the seed regions with significant rsFC changes. This pilot study implies that rituximab may influence both brain structure and connectivity and that GMV changes and rsFC changes are regionally associated.