Nucleus Accumbens In Response Research Articles

Social isolation induces addictive behavior and increases release of dopamine in the <i>nucleus accumbens</i> in response to stimulation of the positive reinforcing zone

The study of the role of social isolation in the pathogenesis of addictive behavior disorders is an important medical and biological problem. Of particular importance are the limitations of social experience in ontogenesis. This work makes an attempt to find a connection between social isolation in ontogenesis and impulsive-compulsive behavior, as an indicator of the premorbid background for gaming and other forms of behavioral addictions. The mechanisms of addictive behavior in rats reared in isolation (IS) were investigated by analyzing the extracellular release of dopamine in response to stimulation of the positive reinforcing zone. Before the experiments, male rats were kept in individual cages from the 21st day of birth to the 90th day. To study elements of addictive behavior, a variant of the Iowa Gambling Task in a 3-arm maze and a method of developing compulsive overeating using intermittent consumption of high-calorie foods were used. To study compulsive behavior, a marble test was used against the background of withdrawal from a high-calorie diet. Surgeries were performed to implant electrodes into the ventral tegmental area (VTA) and the nucleus accumbens in rats exhibiting elements of addictive behavior in the 3-arm maze. These animals were then trained to respond to VTA self-stimulation. Dopamine release was recorded telemetrically in freely moving rats in response to electrical stimulation of the VTA self-stimulation zone. Fast scan cyclic voltammetry was used to determine changes in dopamine levels in the extracellular environment of the nucleus accumbens. IS entered less into the arm with a high degree of probability but with a low reward, and entered more in the arm with a low degree of probability, but with a high reward, which is associated with the appearance of impulsivity in behavior. In the model of compulsive overeating, the number of approaches to the feeder in IS increased, and against the background of withdrawal of high-calorie food, IS were more active in the marble test. In IS exhibiting elements of addictive behavior in the 3-arm maze, the content of extracellular dopamine in response to electrical stimulation of the VTA self-stimulation zones did not reveal any differences compared to the control group of rats with addictive behavior in the maze. At the same time, IS exhibiting elements of addictive behavior in the maze showed a more pronounced dopamine response to a complex stimulus: a conditioned signal used during maze learning light + VTA stimulation. Thus, rearing in the IS causes an increase in dopamine release in the nucleus accumbens in response to stimulation of the positive reinforcement area associated with addictive behaviors: impulsivity and compulsivity. A conclusion is drawn about the prospects of studying the extracellular release of dopamine and assesses addictive behavior disorders caused by limited social contacts in ontogenesis.

Parental styles are associated with eating disorder symptoms, anxiety, interpersonal difficulties, and nucleus accumbens response

ObjectivesEating disorders (EDs) typically emerge during adolescence. Parental bonding has a lasting impact on a child’s mental health during those developmentally critical years. There remains uncertainty over whether parental bonding is a risk factor for developing or maintaining specifically EDs or, rather, general psychopathology and the associated underlying brain function.MethodsForty-one young adult healthy control individuals (HC, 26.6 ± 3.5 years) and 46 individuals with EDs (25 with anorexia nervosa, AN, 22.8 ± 6.4 years, and 21 with bulimia nervosa, BN, 23.5 ± 4.2 years) completed the parental bonding instrument (PBI), assessments for anxiety, depression, and ED behaviors, and underwent a conditioning paradigm during brain imaging.ResultsIn both groups, perceived parental care and overprotection were correlated with state and trait anxiety and interpersonal alienation, and in HC only, with body dissatisfaction and drive for thinness. Individuals with an ED reported lower self-perceived parental care, but higher overprotection compared to the HC group. Nucleus accumbens (NAc) response was related to bonding measures in both groups and right NAc response mediated the relationship between maternal care and trait anxiety in HC.ConclusionsPerceived parental bonding is associated with general psychopathology, including elevated anxiety and interpersonal difficulties across HC and ED groups. Lower perceived parental care and higher overprotection could predispose healthy individuals to develop problems with body shape or weight; however, other, maybe biological factors may determine whether a person will develop an ED. The link between perceived parental bonding, NAc valence processing and anxiety implicates dopaminergic circuits that should be studied further.Level of Evidence: Level III: Case–control analytic study

Estrogen deficiency reduces maximal running capacity and affects serotonin levels differently in the hippocampus and nucleus accumbens in response to acute exercise.

Estrogen deficiency is associated with unfavorable changes in body composition and metabolic health. While physical activity ameliorates several of the negative effects, loss of ovarian function is associated with decreased physical activity levels. It has been proposed that the changes in brain neurochemical levels and /or impaired skeletal muscle function may underlie this phenomenon. We studied the effect of estrogen deficiency induced via ovariectomy (OVX) in female Wistar rats (n = 64). Rats underwent either sham or OVX surgery and were allocated thereafter into four groups matched for body mass and maximal running capacity: sham/control, sham/max, OVX/control, and OVX/max, of which the max groups had maximal running test before euthanasia to induce acute response to exercise. Metabolism, spontaneous activity, and maximal running capacity were measured before (PRE) and after (POST) the surgeries. Three months following the surgery, rats were euthanized, and blood and tissue samples harvested. Proteins were analyzed from gastrocnemius muscle and retroperitoneal adipose tissue via Western blot. Brain neurochemical markers were measured from nucleus accumbens (NA) and hippocampus (HC) using ultra-high performance liquid chromatography. OVX had lower basal energy expenditure and higher body mass and retroperitoneal adipose tissue mass compared with sham group (p ≤ 0.005). OVX reduced maximal running capacity by 17% (p = 0.005) with no changes in muscle mass or phosphorylated form of regulatory light chain (pRLC) in gastrocnemius muscle. OVX was associated with lower serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) level in the NA compared with sham (p = 0.007). In response to acute exercise, OVX was associated with low serotonin level in the HC and high level in the NA (p ≤ 0.024). Our results highlight that OVX reduces maximal running capacity and affects the response of brain neurochemical levels to acute exercise in a brain region-specific manner. These results may offer mechanistic insight into why OVX reduces willingness to exercise.

Metabolic sensing in AgRP regulates sucrose preference and dopamine release in the nucleus accumbens.

Hunger increases the motivation for calorie consumption, often at the expense of low-taste appeal. However, the neural mechanisms integrating calorie-sensing with increased motivation for calorie consumption remain unknown. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus sense hunger, and the ingestion of caloric solutions promotes dopamine release in the absence of sweet taste perception. Therefore, we hypothesised that metabolic-sensing of hunger by AgRP neurons would be essential to promote dopamine release in the nucleus accumbens in response to caloric, but not non-caloric solutions. Moreover, we examined whether metabolic sensing in AgRP neurons affected taste preference for bitter solutions under conditions of energy need. Here we show that impaired metabolic sensing in AgRP neurons attenuated nucleus accumbens dopamine release in response to sucrose, but not saccharin, consumption. Furthermore, metabolic sensing in AgRP neurons was essential to distinguish nucleus accumbens dopamine response to sucrose consumption when compared with saccharin. Under conditions of hunger, metabolic sensing in AgRP neurons increased the preference for sucrose solutions laced with the bitter tastant, quinine, to ensure calorie consumption, whereas mice with impaired metabolic sensing in AgRP neurons maintained a strong aversion to sucrose/quinine solutions despite ongoing hunger. In conclusion, we demonstrate normal metabolic sensing in AgRP neurons drives the preference for calorie consumption, primarily when needed, by engaging dopamine release in the nucleus accumbens.

Genetic variation in endocannabinoid signaling: Anxiety, depression, and threat- and reward-related brain functioning during the transition into adolescence

BackgroundThe endocannabinoid system modulates neural activity throughout the lifespan. In adults, neuroimaging studies link a common genetic variant in fatty acid amide hydrolase (FAAH C385A)—an enzyme that regulates endocannabinoid signaling—to reduced risk of anxiety and depression, and altered threat- and reward-related neural activity. However, limited research has investigated these associations during the transition into adolescence, a period of substantial neurodevelopment and increased psychopathology risk. MethodsThis study included FAAH genotype and longitudinal neuroimaging and neurobehavioral data from 4811 youth (46% female; 9–11 years at Baseline, 11–13 years at Year 2) from the Adolescent Brain Cognitive DevelopmentSM Study. Linear mixed models examined the effects of FAAH and the FAAH x time interaction on anxiety and depressive symptoms, amygdala reactivity to threatening faces, and nucleus accumbens (NAcc) response to happy faces during the emotional n-back task. ResultsA significant main effect of FAAH on depressive symptoms was observed, such that depressive symptoms were lower across both timepoints in those with the AA genotype compared to both AC and CC genotypes (p’s<0.05). There were no significant FAAH x time interactions for anxiety, depression, or neural responses (p’s>0.05). Additionally, there were no main effects of FAAH on anxiety or neural responses (p’s>0.05). ConclusionsOur findings add to emerging evidence linking the FAAH C385A variant to lower risk of psychopathology, and extend these findings to a developmental sample. In particular, we found lower depressive symptoms in FAAH AA genotypes compared to AC and CC genotypes. Future research is needed to characterize the role of the FAAH variant and the eCB system more broadly in neurodevelopment and psychiatric risk.

Neural similarity in nucleus accumbens during decision-making for the self and a best friend: Links to adolescents' self-reported susceptibility to peer influence and risk taking.

Adolescence is marked by increased peer influence on risk taking; however, recent literature suggests enormous individual variation in peer influence susceptibility to risk-taking behaviors. The current study uses representation similarity analysis to test whether neural similarity between decision-making for self and peers (i.e., best friends) in a risky context is associated with individual differences in self-reported peer influence susceptibility and risky behaviors in adolescents. Adolescent participants (N = 166, Mage = 12.89) completed a neuroimaging task in which they made risky decisions to receive rewards for themselves, their best friend, and their parents. Adolescent participants self-reported peer influence susceptibility and engagement in risk-taking behaviors. We found that adolescents with greater similarity in nucleus accumbens (NACC) response patterns between the self and theirbest friend reported greater susceptibility to peer influence and increased risk-taking behaviors. However, neural similarity in ventromedial prefrontal cortex (vmPFC) was not significantly associated with adolescents' peer influence susceptibility and risk-taking behaviors. Further, when examining neural similarity between adolescents' self and their parent in the NACC and vmPFC, we did not find links to peer influence susceptibility and risk-taking behaviors. Together, our results suggest that greater similarity for self and friend in the NACC is associated with individual differences in adolescents' peer influence susceptibility and risk-taking behaviors.

Neural representation and modulation of volitional motivation in response to escalating efforts.

Task-dependent volitional control of the selected neural activity in the cortex is critical to neuroprosthetic learning to achieve reliable and robust control of the external device. The volitional control of neural activity is driven by a motivational factor (volitional motivation), which directly reinforces the target neurons via real-time biofeedback. However, in the absence of motor behaviour, how do we evaluate volitional motivation? Here, we defined the criterion (ΔF/F) of the calcium fluorescence signal in a volitionally controlled neural task, then escalated the efforts by progressively increasing the number of reaching the criterion or holding time after reaching the criterion. We devised calcium-based progressive threshold-crossing events (termed 'Calcium PTE') and calcium-based progressive threshold-crossing holding-time (termed 'Calcium PTH') for quantitative assessment of volitional motivation in response to progressively escalating efforts. Furthermore, we used this novel neural representation of volitional motivation to explore the neural circuit and neuromodulator bases for volitional motivation. As with behavioural motivation, chemogenetic activation and pharmacological blockade of the striatopallidal pathway decreased and increased, respectively, the breakpoints of the 'Calcium PTE' and 'Calcium PTH' in response to escalating efforts. Furthermore, volitional and behavioural motivation shared similar dopamine dynamics in the nucleus accumbens in response to trial-by-trial escalating efforts. In general, the development of a neural representation of volitional motivation may open a new avenue for smooth and effective control of brain-machine interface tasks. KEY POINTS: Volitional motivation is quantitatively evaluated by M1 neural activity in response to progressively escalating volitional efforts. The striatopallidal pathway and adenosine A2A receptor modulate volitional motivation in response to escalating efforts. Dopamine dynamics encode prediction signal for reward in response to repeated escalating efforts during motor and volitional conditioning. Mice learn to modulate neural activity to compensate for repeated escalating efforts in volitional control.

Reduced dopamine release in Dcc haploinsufficiency male mice abolishes the rewarding effects of cocaine but not those of morphine and ethanol.

The Netrin-1/DCC guidance cue pathway is critically involved in the adolescent organization of the mesocorticolimbic dopamine circuitry. Adult mice heterozygous for Dcc show reduced dopamine release in the nucleus accumbens in response to amphetamine and, in turn, blunted sensitivity to the rewarding effects of this drug. Here, we tested whether the protective effects of Dcc haploinsufficiency are specific to stimulant drugs of abuse or instead extrapolate to opioids and ethanol. We used the place preference paradigm to measure the rewarding effects of cocaine (20mg/kg), morphine (5 or 10mg/Kg), or ethanol (20%) in adult (PND 75) male Dcc haploinsufficient mice or their wild-type litter mates. In a second experiment, we compared in these two genotypes, in vivo dopamine release in the nucleus accumbens after a single i.p. injection of morphine (10mg/kg). We found reduced morphine-induced dopamine release in the nucleus accumbens of Dcc haploinsufficient male mice, but, contrary to the effects of stimulant drugs, there is no effect of genotype on morphine-induced conditioned preference. These findings show that reduced drug-induced mesolimbic dopamine in Dcc haploinsufficient male mice protects specifically against the rewarding effects of stimulant drugs, but not against the rewarding properties of morphine and ethanol. These results suggest that these drugs exert their rewarding effect via different brain circuits.

Replication of neural responses to monetary incentives and exploration of reward-influenced network connectivity in fibromyalgia

Neuroimaging research has begun to implicate alterations of brain reward systems in chronic pain. Previously, using functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task, Martucci et al. (2018) showed that neural responses to reward anticipation and outcome are altered in fibromyalgia. In the present study, we aimed to test the replicability of these altered neural responses to reward in a separate fibromyalgia cohort. In addition, the present study was conducted at a distinct U.S. location but involved a similar study design. For the present study, 20 patients with fibromyalgia and 20 healthy controls participated in MID task fMRI scan procedures and completed clinical/psychological questionnaires. fMRI analyses comparing patient and control groups revealed a consistent trend of main results which were largely similar to the prior reported results. Specifically, in the replication fibromyalgia cohort, medial prefrontal cortex (MPFC) response was reduced during gain anticipation and was increased during no-loss (non-punishment) outcome compared to controls. Also consistent with previous findings, the nucleus accumbens response to gain anticipation did not differ in patients vs. controls. Further, results from similarly-designed behavioral, correlational, and exploratory analyses were complementary to previous findings. Finally, a novel network-based functional connectivity analysis of the MID task fMRI data across patients vs. controls implied enhanced connectivity within the default mode network in participants with fibromyalgia. Together, based on replicating prior univariate results and new network-based functional connectivity analyses of MID task fMRI data, we provide further evidence of altered brain reward responses, particularly in the MPFC response to reward outcomes, in patients with fibromyalgia.

Nucleus Accumbens Response to Reward among Children with a Family History of Alcohol Use Problems: Convergent Findings from the ABCD Study® and Michigan Longitudinal Study.

Having a family history of alcohol use problems (FH+) conveys risk for alcohol use in offspring. Reward-related brain functioning may play a role in this vulnerability. The present study investigated brain function in the nucleus accumbens (NAcc) associated with the anticipation of reward in youth with two biological parents with alcohol use problems (FH+2), one biological parent with alcohol use problems (FH+1), and no biological parents with alcohol use problems (FH-). Participants were from the large, national Adolescent Brain Cognitive Development (ABCD) Study (mean age: 9.93; 48% female; FH+2 n = 223, FH+1 n = 1447, FH- n = 9690) and the Michigan Longitudinal Study (MLS), consisting of community-recruited families with high rates of alcohol use disorder (mean age: 10.54; 39.3% female; FH+2 n = 40, FH+1 n = 51, FH- n = 40). Reward anticipation was measured by the monetary incentive delay task. Regression models were used to assess associations between FH status and the anticipation of large rewards in right and left NAcc regions of interest. In both studies, FH+2 youth showed blunted anticipatory reward responding in the right NAcc compared to FH+1 youth. In the MLS, FH+2 youth also had blunted anticipatory reward responding in the right NAcc compared to the FH- group. Convergent results across two separate samples provide insights into a unique vulnerability of FH+2 youth and suggest that binary FH+ versus FH- categorizations may obscure important differences within FH+ youth.

Multi-modal assessment of reward functioning in adolescent anhedonia.

Anhedonia is a core symptom of depression that predicts worse treatment outcomes. Dysfunction in neural reward circuits is thought to contribute to anhedonia. However, whether laboratory-based assessments of anhedonia and reward-related neural function translate to adolescents' subjective affective experiences in real-world contexts remains unclear. We recruited a sample of adolescents (n = 82; ages 12-18; mean = 15.83) who varied in anhedonia and measured the relationships among clinician-rated and self-reported anhedonia, behaviorally assessed reward learning ability, neural response to monetary reward and loss (as assessed with functional magnetic resonance imaging), and repeated ecological momentary assessment (EMA) of positive affect (PA) and negative affect (NA) in daily life. Anhedonia was associated with lower mean PA and higher mean NA across the 5-day EMA period. Anhedonia was not related to impaired behavioral reward learning, but low PA was associated with reduced nucleus accumbens response during reward anticipation and reduced medial prefrontal cortex (mPFC) response during reward outcome. Greater mean NA was associated with increased mPFC response to loss outcome. Traditional laboratory-based measures of anhedonia were associated with lower subjective PA and higher subjective NA in youths' daily lives. Lower subjective PA and higher subjective NA were associated with decreased reward-related striatal functioning. Higher NA was also related to increased mPFC activity to loss. Collectively, these findings demonstrate that laboratory-based measures of anhedonia translate to real-world contexts and that subjective ratings of PA and NA may be associated with neural response to reward and loss.

156-OR: Central Neural Processing of Sweet Taste Is Altered following Bariatric Surgery

Bariatric surgery causes marked changes in eating behavior, including reduced preference for highly sweet foods. No studies have addressed the brain response to receipt of this primary taste modality following weight loss surgery. Eighteen women (BMI 47.5±7.6 kg/m2, age 43.1±10.2 y) rated perceived intensity and liking of sucrose solutions (0, 0.1, 0.4, 0.86 &amp; 1.M) in a three-block randomized design, and underwent functional magnetic resonance imaging (fMRI) to assess brain responses to 0.40 M and 0.M sucrose sprayed onto the tongue relative to water (14 sucrose and 34 water trials in two 5:52 min long scans) , before and after bariatric surgery-induced weight loss. Eight women underwent Roux-en-Y and had sleeve gastrectomy. The post-surgery visit occurred 4.7 months (range 3-9) following the pre-surgery assessment. BMI was significantly reduced to 38.0±7.8 kg/m2. There was no effect of weight loss on rated sucrose solution intensity. However, post-surgical “preferred sweetness” of the test solutions was significantly lower (0.53±0.12 vs. 0.22±0.M; p&amp;lt;0.008) . Across the whole sample (pre- and post-surgery) , both sucrose concentrations relative to water activated bilateral insula and lateral frontal/orbitofrontal areas (p&amp;lt;0.001, k=5) . However, only 0.4M sucrose elicited the left nucleus accumbens (NAc) response (pFW E=0.005, k=17, family wise error-corrected within a bilateral NAc mask) . Pre-surgery activations included the anterior cingulate cortex (ACC) and bilateral insula as well as NAc (left: p=0.001, k=33; right p=0.009, k=17) . Post-surgery activations were present only in the ACC and bilateral insula. NAc responses were significantly greater pre-surgery relative to post-surgery (pFWE =0.026, k=6) . These data strongly suggest that bariatric surgery significantly affects central neural processing of sweet taste. While salience-assigning ACC and insula responses did not differ, nucleus accumbens region coding reward responded less post-surgically. Disclosure J.Alessi: None. K.Sawin: None. G.D.Chittum: None. S.E.Oswalt: None. M.Dzemidzic: None. D.A.Kareken: None. R.V.Considine: Other Relationship; Lilly. Funding American Diabetes Association (1-18-ICTS-036)

Residence in High-Crime Neighborhoods Moderates the Association Between Interleukin 6 and Social and Nonsocial Reward Brain Responses

BackgroundResidence in high-crime neighborhoods, especially in childhood, is linked to mental health issues later. Detecting distinct neurobiological processes underlying the effects of this environmental stressor may be critical to identifying prevention and intervention targets. This study examined the relationships of levels of a circulating inflammatory protein with social and monetary reward–related brain function among adolescents who lived in high- versus low-crime neighborhoods during childhood. MethodsA total of 70 participants (mean age = 16.3 years; 57% female) completed measures of inflammatory markers, depression history, and health and 2 functional magnetic resonance imaging tasks assessing responsivity to monetary and social rewards. Multivariate linear regression tested whether individuals with higher interleukin 6, an inflammatory cytokine, who also lived in neighborhoods with higher crime had distinct orbitofrontal cortex and nucleus accumbens activation to monetary reward and social acceptance. ResultsFor adolescents who lived in neighborhoods with more crime, higher interleukin 6 was associated with higher nucleus accumbens responses to social acceptance. We did not detect significant moderating effects of neighborhood crime rates on the associations of interleukin 6 with orbitofrontal cortex responses to social acceptance or orbitofrontal cortex/nucleus accumbens activation during monetary reward anticipation or outcome. These results were obtained before and after adjusting for neighborhood income and other covariates. We did not detect significant moderating effects of neighborhood income. ConclusionsHigh-threat residence environment and specific demands of the social context in childhood may have shaped the effect of peripheral immune activation on reward-related neural function in adolescence. The prevailing view that inflammation-associated behaviors are characterized by blunted responsiveness to reward may be oversimplistic.

Family Socioeconomic Status and Children’s Nucleus Accumbens Response to Loss Anticipation: Racial Differences

Objective: Socioeconomic Status (SES) and race (as a proxy of racism) may have overlapping effects on substance use and related brain mechanisms such as nucleus accumbens function. Therefore, we hypothesized that nucleus accumbens function might be jointly affected by race and SES. Materials and Methods: The Adolescent Brain Cognitive Development (ABCD) study baseline data was used for this cross-sectional study. The study included 7791 children between the ages of 9 and 10. The independent variable was parental education as our SES indicator of interest. The moderator was race as a social factor rather than a biological factor. The confounders included sex, age, ethnicity, and family structure. The outcome variable was nucleus accumbens function measured using functional MRI (fMRI). We used mixedeffects regression models with and without race by SES interactions to analyze the data. Results: Children with higher parental education had lower nucleus accumbens function during loss anticipation (conceptualized as a risk factor of substance use). However, this effect was larger for White children than it was for Black children. Thus, the effects of race and SES on nucleus accumbens function were multiplicative rather than additive. Conclusion: Children’s race and SES have implications for nucleus accumbens function. The results are important because nucleus accumbens function may correlate with future substance use. However, SES effects on nucleus accumbens function may differ by race, explaining why the risk of substance use remains high in high SES Black youth.

Effects of intranasal oxytocin on threat- and reward-related functional connectivity in men and women with and without childhood abuse-related PTSD

Novel treatments that target neurobiological alterations associated with childhood trauma, particularly among those with posttraumatic stress disorder (PTSD), could mitigate negative outcomes for these at-risk individuals. PTSD is characterized by abnormalities within the brain's salience network and reward circuitry, which are modulated by intranasal oxytocin. Using a double-blind, randomized, placebo-controlled crossover design, we tested whether intranasal oxytocin (24 international units) influenced functional coupling of the amygdala with the anterior insula (AI), dorsal anterior cingulate cortex, and nucleus accumbens in response to implicitly presented fearful, angry, and happy faces among childhood trauma-exposed individuals with (n = 16, 9 women) and without PTSD (n = 18, 12 women). Psychophysiological interaction analyses revealed that oxytocin effects were limited to amygdala-AI connectivity in the fear condition, distinct for men and women, and not impacted by PTSD diagnosis. In response to fear faces, oxytocin reduced left amygdala-left AI connectivity for women but not men; reduced left amygdala-right AI connectivity among women, but increased this connectivity in men; and reduced right amygdala-right anterior insula connectivity for men, but increased it for women. Results suggest that intranasal oxytocin modulates threat salience among childhood trauma-exposed individuals and that these effects vary as a function of gender and hemisphere.

Parental Education and Nucleus Accumbens Response to Reward Anticipation: Minorities' Diminished Returns.

Considerable research has documented the effects of race and socioeconomic status (SES) on reward-seeking behaviors; however, less is known about the multiplicative effects of race and family SES on brain response to reward anticipation. Marginalization-related Diminished Returns (MDRs) suggest that family SES would show weaker effects on brain development of children in non-White families than in White families. To test race by SES variation in Nucleus Accumbens (NAcc) response to reward anticipation (NAcc-RA) among American children. For this cross-sectional analysis, data came from the Adolescent Brain Cognitive Development (ABCD) study which included 6,419, 9-10 year old children. The independent variable was parental education. The moderator was race. The primary outcome was the right NAcc-RA. Age, sex, ethnicity, household income, and family structure were the covariates. We used mixed effects regression models that adjusted for the nested nature of the ABCD data. While high parental education was associated with a higher amount of right NAcc-RA, this effect was stronger for White than non-White children. This finding was evident in the observed interactions between race and parental education on the right NAcc-RA. For American children, NAcc-RA is not shaped by race or family SES, but by their intersection. As a result of the interaction between race and SES (diminished return of SES for non-Whites), middle-class racial minority children may remain susceptible to high-risk behaviors. Disparities in high-risk behaviors in children should not be reduced to economic disparities. Structural inequalities may reduce the return of SES resources for non-White families.

Roles of dopamine and glutamate co-release in the nucleus accumbens in mediating the actions of drugs of abuse.

Projections of ventral tegmental area dopamine (DA) neurons to the medial shell of the nucleus accumbens have been increasingly implicated as integral to the behavioral and physiological changes involved in the development of substance use disorders (SUDs). Recently, many of these nucleus accumbens-projecting DA neurons were found to also release the neurotransmitter glutamate. This glutamate co-release from DA neurons is critical in mediating the effect of drugs of abuse on addiction-related behaviors. Potential mechanisms underlying the role(s) of dopamine/glutamate co-release in contributing to SUDs are unclear. Nevertheless, an important clue may relate to glutamate's ability to potentiate loading of DA into synaptic vesicles within terminals in the nucleus accumbens in response to drug-induced elevations in neuronal activity, enabling a more robust release of DA after stimulation. Here, we summarize how drugs of abuse, particularly cocaine, opioids, and alcohol, alter DA release in the nucleus accumbens medial shell, examine the potential role of DA/glutamate co-release in mediating these effects, and discuss future directions for further investigating these mechanisms.

Sex and strain differences in dynamic and static properties of the mesolimbic dopamine system.

Sex is a biological variable that contributes to the incidence, clinical course, and treatment outcome of brain disorders. Chief among these are disorders associated with the dopamine system. These include Parkinson's disease, ADHD, schizophrenia, and mood disorders, which show stark differences in prevalence and outcome between men and women. In order to reveal the influence of biological sex as a risk factor in these disorders, there is a critical need to collect fundamental information about basic properties of the dopamine system in males and females. In Long Evans rats, we measured dynamic and static properties related to the mesolimbic dopamine system. Static measures included assessing ventral tegmental area (VTA) dopamine cell number and volume and expression of tyrosine hydroxylase and dopamine transporter. Dynamic measures in behaving animals included assessing (1) VTA neuronal encoding during learning of a cue-action-reward instrumental task and (2) dopamine release in the nucleus accumbens in response to electrical stimulation of the VTA, vesicular depletion of dopamine, and amphetamine. We found little or no sex difference in these measures, suggesting sexual congruency in fundamental static and dynamic properties of dopamine neurons. Thus, dopamine related sex-differences are likely mediated by secondary mechanisms that flexibly influence the function of the dopamine cells and circuits. Finally, we noted that most behavioral sex differences had been reported in Sprague-Dawley rats and repeated some of the above measures in that strain. We found some sex differences in those animals highlighting the importance of considering strain differences in experimental design and result interpretation.

Longitudinal Trajectories of Post-Election Distress Track Changes in Neural and Psychological Functioning.

The shift in political climate after the 2016 U.S. presidential election had a distressing effect on many individuals. To date, no research has identified how changes in societal-level distressing experiences affected ongoing neurobiological and psychological functioning. Fifty-five participants (Mage = 21.746, 37 women) were tested at two time points. fMRI and psychological measures were used to test the hypotheses that increases in distress over 1 year would relate to worsening mental health symptomology and blunted neurobiological response to reward during the same period. Because individual experiences of distress occurred within a larger macroclimate of societal attitudes, measures were standardized to reflect relative change within the sample. Distress changes over 1 year were positively associated with problematic mental health symptomology and nucleus accumbens (NAcc) response to reward, with dissociable effects for anticipation and outcome. Worsening distress was associated with increased NAcc response to reward anticipation but decreased NAcc response to reward outcome. Individuals who exhibited increased sensitivity to anticipatory reward were those who exhibited more avoidance distress symptoms, whereas intrusion and hyperarousal were associated with decreased sensitivity to reward outcome. This study highlights the importance of considering individual variation in profiles of change in response to ongoing distress, suggests that individual response styles yield differences in reward sensitivity, and extends neurobiological understanding of exposure to stressful life experiences to political events.

Brain Reward System Dysfunction in Adolescence: Current, Cumulative, and Developmental Periods of Depression.

Reward system dysfunction is a well-known correlate and predictor of depression in adults and adolescents, with depressed individuals showing blunted (hyporeactive) striatal response to monetary rewards. Furthermore, studies of remitted depression suggest network-wide hyporeactivity of striatal (caudate, putamen, nucleus accumbens) and cortical (insula, anterior cingulate cortex [ACC]) regions even in the absence of current symptoms. Thus, it remains unclear which patterns of hyporeactivity represent a trait-like indicator of depression and which represent a current depressed state. The authors examined the relationships between regions of a cortico-striatal circuit supporting reward processing and both current depression and cumulative depression history. Using a functional MRI monetary reward task, the authors measured brain response to monetary gains and losses in a longitudinal sample of adolescents (N=131) who had been annually assessed for psychiatric symptoms since ages 3-5 years. Current depression severity was associated with hyporeactivity exclusively in the nucleus accumbens in response to the anticipation of a reward, while cumulative depression severity was associated with blunted response to anticipation across a cortico-striatal circuit (striatum, ACC, insula). Follow-up analyses investigating the effects of depression on reward processing at different developmental stages revealed a similar pattern: recent depression severity during adolescence was associated with more focal hyporeactivity in the nucleus accumbens, while depression severity during early childhood (i.e., preschool) was associated with more global hyporeactivity across the cortico-striatal circuit. The study findings indicate important distinctions between disruptions in reward system neural circuitry associated with a history of depression (particularly early-onset depression) and current depression. These results have implications for understanding the etiology and treatment of reward processing deficits in depression.