Reward Processing Research Articles

Age-related changes of dopamine D1 and D2 receptors expression in parvalbumin-positive cells of the orbitofrontal and prelimbic cortices of mice.

Dopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these processes. Parvalbumin-positive (PV+) neurons are one of the major classes of inhibitory GABAergic neurons in the cortex, they modulate the activity of neighboring neurons, influencing various brain functions. While DA receptor expression exhibits age-related changes, the age-related changes of these receptors in PV+ neurons, especially in the PFC, remain unclear. To address this, we investigated the expression of DA D1 (D1R) and D2 (D2R) receptors in PV+ neurons within the orbitofrontal (OFC) and prelimbic (PrL) cortices at different postnatal ages (P28, P42, P56, and P365). We found that the expression of D1R and D2R in PV+ neurons showed both age- and region-related changes. PV+ neurons in the OFC expressed a higher abundance of D1 than those in the PrL, and those neurons in the OFC also showed higher co-expression of D1R and D2R than those in the PrL. In the OFC and PrL, D1R in PV+ neurons increased from P28 and reached a plateau at P42, then receded to express at P365. Meanwhile, D2R did not show significant age-related changes between the two regions except at P56. These results showed dopamine receptors in the prefrontal cortex exhibit age- and region-specific changes, which may contribute to the difference of these brain regions in reward-related brain functions.

Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.

Experience-dependent regulation of dopaminergic signaling in the somatosensory cortex

Dopamine critically influences reward processing, sensory perception, and motor control. Yet, the modulation of dopaminergic signaling by sensory experiences is not fully delineated. Here, by manipulating sensory experience using bilateral single-row whisker deprivation, we demonstrated that gene transcription in the dopaminergic signaling pathway (DSP) undergoes experience-dependent plasticity in both granular and supragranular layers of the primary somatosensory (barrel) cortex (S1). Sensory experience and deprivation compete for the regulation of DSP transcription across neighboring cortical columns, and sensory deprivation-induced changes in DSP are topographically constrained. These changes in DSP extend beyond cortical map plasticity and influence neuronal information processing. Pharmacological regulation of D2 receptors, a key component of DSP, revealed that D2 receptor activation suppresses excitatory neuronal excitability, hyperpolarizes the action potential threshold, and reduces the instantaneous firing rate. These findings suggest that the dopaminergic drive originating from midbrain dopaminergic neurons, targeting the sensory cortex, is subject to experience-dependent regulation and might create a regulatory feedback loop for modulating sensory processing. Finally, using topological gene network analysis and mutual information, we identify the molecular hubs of experience-dependent plasticity of DSP. These findings provide new insights into the mechanisms by which sensory experience shapes dopaminergic signaling in the brain and might help unravel the sensory deficits observed after dopamine depletion.

Task-induced deactivation dysfunction during reward processing is associated with low self-esteem in a possible subtype of major depression.

Low self-esteem is a frequent symptom in major depressive disorder (MDD). This functional magnetic resonance imaging study investigated whether MDD patients with low self-esteem show a distinct neural pathophysiology. Previous studies linked low self-esteem to reduced task-induced deactivation of the pregenual anterior cingulate cortex (pgACC) as a part of the default mode network, and to reduced connectivity between pgACC and reward system. Goya-Maldonado etal. identified an MDD subtype with pgACC and ventral striatal overactivations during reward processing. We hypothesized that this subtype might be characterized by low self-esteem. Eighty-three MDD patients performed the desire-reason dilemma task and completed the Rosenberg Self-Esteem Scale (RSES). Brain activity during bottom-up reward processing was regressed upon the RSES scores, controlling for depression severity measured by the Montgomery-Åsberg Depression Rating Scale. To corroborate the findings, we compared self-esteem scores between patient subgroups with impaired task-induced deactivation (n=31) and with preserved task-induced deactivation (n=31) of the pgACC. Consistent with our a priori hypothesis, activity in a bilateral fronto-striatal network including pgACC and ventral striatum correlated negatively with RSES scores, also when controlling for depression severity. In the additional analysis, patients with impaired task-induced pgACC deactivation showed lower self-esteem (t (52.82)=-2.27; p=.027, d=0.58) compared to those with preserved task-induced pgACC deactivation. We conclude that low self-esteem in MDD patients is linked to a task-induced deactivation dysfunction of the pgACC. Our findings suggest that a previously described possible subtype of MDD with pgACC and ventral striatal overactivations during reward processing is clinically characterized by low self-esteem.

Assessing midbrain neuromelanin and its relationship to reward learning in anorexia nervosa: Stage 1 of a registered report.

Anorexia nervosa (AN) is a debilitating and potentially chronic eating disorder, characterized by low hedonic drive toward food, which has been linked with perturbations in both reward processing and dopaminergic activity. Neuromelanin-sensitive magnetic resonance imaging (MRI) is an emerging method to index midbrain neuromelanin-a by-product of dopaminergic synthesis. The assessment of midbrain neuromelanin, and its association with AN psychopathology and reward-related processes, may provide critical insights into reward circuit function in AN. This study will incorporate neuromelanin-sensitive MRI into an existing study of appetitive conditioning in those with AN. Specifically, those with acute and underweight AN (N=30), those with weight-restored AN (N=30), and age-matched healthy controls (N=30) will undergo clinical assessment of current and previous psychopathology, in addition to structural neuromelanin-sensitive MRI, diffusion MRI, and functional MRI (fMRI) during appetitive conditioning. This study will be among the first to interrogate midbrain neuromelanin in AN-a disorder characterized by altered dopaminergic activity. Results will help establish whether abnormalities in the midbrain synthesis of dopamine are evident in those with AN and are associated with symptomatic behavior and reduced ability to experience pleasure and reward.

An Expanded Conceptual Framework for Understanding Irritability in Childhood: The Role of Cognitive Control Processes

Children prone to irritability experience significant functional impairments and internalising and externalising problems. Contemporary models have sought to elucidate the underlying mechanisms in irritability, such as aberrant threat and reward biases to improve interventions. However, the cognitive control processes that underlie threat (e.g., attention towards threats) and reward (e.g., attention towards reward-related cues) biases and the factors which influence the differential activation of positive and negative valence systems and thus leading to maladaptive activation of cognitive control processes (i.e., proactive and reactive control) are unclear. Thus, we aim to integrate extant theoretical and empirical research to elucidate the cognitive control processes underlying threat and reward processing that contribute to irritability in middle childhood and provide a guiding framework for future research and treatment. We propose an expanded conceptual framework of irritability that includes broad intraindividual and environmental vulnerability factors and propose proximal ‘setting’ factors that activate the negative valence and positive valence systems and proactive and reactive cognitive control processes which underpin the expression and progression of irritability. We consider the implications of this expanded conceptualisation of irritability and provide suggestions for future research.

Task–Rest Reconfiguration Efficiency of the Reward Network Across Adolescence and Its Association With Early Life Stress and Depressive Symptoms

Adolescents face significant changes in many domains of their daily lives that require them to flexibly adapt to changing environmental demands. To shift efficiently among various goals, adolescents must reconfigure their brains, disengaging from previous tasks and engaging in new activities. To examine this reconfiguration, we obtained resting-state and task-based functional magnetic resonance imaging (fMRI) scans in a community sample of 164 youths. We assessed the similarity of functional connectivity (FC) of the reward network between resting state and a reward-processing state, indexing the degree of reward network reconfiguration required to meet task demands. Given research documenting relations among reward network function, early life stress (ELS), and adolescent depression, we examined the association of reconfiguration efficiency with age across adolescence, the moderating effect of ELS on this association, and the relation between reconfiguration efficiency and depressive symptoms. We found that older adolescents showed greater reconfiguration efficiency than younger adolescents and, furthermore, that this age-related association was moderated by the experience of ELS. These findings suggest that reconfiguration efficiency of the reward network increases over adolescence, a developmental pattern that is attenuated in adolescents exposed to severe ELS. In addition, even after controlling for the effects of age and exposure to ELS, adolescents with higher levels of depressive symptoms exhibited greater reconfiguration efficiency, suggesting that they have brain states at rest that are more strongly optimized for reward processing than do asymptomatic youth. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science.

Impaired social reward processing in individuals with Internet gaming disorder and its relationship with early face perception

Previous research has found that individuals with Internet gaming disorder (IGD) show different patterns of social function impairments in game-related and real-life social contexts. Impaired social reward processing may be the underlying mechanism according to the Social Motivation Theory. Thus, in this study, event-related potentials were recorded from 24 individuals with IGD and 24 healthy gamers during a social judgement task. We focused on reward positivity (RewP) elicited by game-related and real-life social rewards, and N170 elicited by game avatar faces and real faces. These indicators were used to explore the neurocognitive mechanism of impaired social reward processing in individuals with IGD and its relationship with early face perception. Results showed that (1) the RewP elicited by real-life social reward was considerably reduced in individuals with IGD relative to healthy gamers. (2) The N170 elicited by game avatar faces in individuals with IGD was larger than that elicited by real faces. However, the N170 was not associated with RewP in either group. (3) The score for IGD severity was correlated with the RewP elicited by real-life social reward and the N170 elicited by game avatar face. In conclusion, the present study suggests that the impaired social reward processing in individuals with IGD is mainly manifested in a decreased neural sensitivity to real-life social reward. Meanwhile, the reduced RewP elicited by real-life social reward and the enhanced N170 elicited by game avatar face might serve as potential biomarkers for IGD.

Modulation of habenular and nucleus accumbens functional connectivity by ketamine in major depression.

Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Since ketamine elicits rapid antidepressant and antianhedonic effects in MDD, this study sought to investigate how serial ketamine infusion (SKI) treatment modulates static and dynamic functional connectivity (FC) in Hb and NAc functional networks. MDD participants (n=58, mean age=40.7 years, female=28) received four ketamine infusions (0.5mg/kg) 2-3 times weekly. Resting-state functional magnetic resonance imaging (fMRI) scans and clinical assessments were collected at baseline and 24h post-SKI. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Changes in FC pre-to-post SKI, and correlations with changes with mood and anhedonia were examined. Comparisons of FC between patients and healthy controls (HC) at baseline (n=55, mean age=32.6, female=31), and between HC assessed twice (n=16) were conducted as follow-up analyses. Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in mood ratings. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. No differences were observed between HC at baseline or over time. Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions in MDD. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.

Reward learning capacity in a community sample of individuals who use cannabis.

Cannabis use has been linked to deficient reward processing; however, little is known about its relation to the specific construct of reward learning, in which behavior is modified through associating novel stimuli with a positive outcome. The probabilistic reward task was used to objectively evaluate reward learning in 38 individuals who use recreational cannabis and 34 control comparison participants from the community. Reward learning was evidenced by the development of a response bias, which indicates the propensity to modulate behavior as a function of prior reinforcement. Both cannabis and control groups demonstrated reward learning, with no group differences in response bias development. Among cannabis participants, trending significant relationships between greater chronicity, r(36) = -.30, p = .077, self-reported potency, r(19) = -.33, p = .052, and poorer reward learning were found. Nonsignificant relationships were found between reward learning and frequency, age of initiation, weekly quantity or Cannabis Use Disorder Identification Test-Revised (CUDIT-R) scores (all p > .05). The ability to form noncannabis reward associations is promising for the success of therapeutic interventions for problematic cannabis use; however, indications of severity of use in relation to poorer reward learning suggests a need for a better pharmacological and pharmacokinetic understanding of cannabis. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Reward-Related Brain Activity Mediates the Relationship Between Decision-Making Deficits and Pediatric Depression Symptom Severity

BackgroundThe mechanisms that link neural and behavioral indices of reduced reward sensitivity in depression, particularly in children, remain unclear. Reward positivity (RewP), a neural index of reward processing, has been consistently associated with depression. Separately, recent studies using the drift-diffusion model on behavioral data have delineated computational indices of reward sensitivity. Therefore, in the current study, we examined whether RewP is a neural mediator of drift-diffusion model–based indices of reward processing in predicting pediatric depression across varying levels of symptom severity. MethodsA community sample of 166 girls, ages 8 to 14 years, completed 2 tasks. The first was a reward guessing task from which RewP was computed using electroencephalography; the second was a probabilistic reward-based decision-making task. On this second task, drift-diffusion model analysis was applied to behavioral data to quantify the efficiency of accumulating reward-related evidence (drift rate) and potential baseline bias (starting point) toward the differently rewarded choices. Depression severity was measured using the self-report Children’s Depression Inventory. ResultsRewP was correlated with drift rate, but not starting point bias, toward the more rewarded choice. Furthermore, RewP completely mediated the association between a slower drift rate toward the more rewarded option and higher depression symptom severity. ConclusionsOur findings suggest that reduced neural sensitivity to reward feedback may be a neural mechanism that underlies behavioral insensitivity to reward in children and adolescents with higher depression symptom severity, offering novel insights into the relationship between neural and computational indices of reward processing in this context.

Robust memory of face moral values is encoded in the human caudate tail: a simultaneous EEG-fMRI study

Moral judgements about people based on their actions is a key component that guides social decision making. It is currently unknown how positive or negative moral judgments associated with a person’s face are processed and stored in the brain for a long time. Here, we investigate the long-term memory of moral values associated with human faces using simultaneous EEG-fMRI data acquisition. Results show that only a few exposures to morally charged stories of people are enough to form long-term memories a day later for a relatively large number of new faces. Event related potentials (ERPs) showed a significant differentiation of remembered good vs bad faces over centerofrontal electrode sites (value ERP). EEG-informed fMRI analysis revealed a subcortical cluster centered on the left caudate tail (CDt) as a correlate of the face value ERP. Importantly neither this analysis nor a conventional whole-brain analysis revealed any significant coding of face values in cortical areas, in particular the fusiform face area (FFA). Conversely an fMRI-informed EEG source localization using accurate subject-specific EEG head models also revealed activation in the left caudate tail. Nevertheless, the detected caudate tail region was found to be functionally connected to the FFA, suggesting FFA to be the source of face-specific information to CDt. A further psycho-physiological interaction analysis also revealed task-dependent coupling between CDt and dorsomedial prefrontal cortex (dmPFC), a region previously identified as retaining emotional working memories. These results identify CDt as a main site for encoding the long-term value memories of faces in humans suggesting that moral value of faces activates the same subcortical basal ganglia circuitry involved in processing reward value memory for objects in primates.

EPPE: An Efficient Progressive Policy Enhancement framework of deep reinforcement learning in path planning

Path planning is a key process in robotics, playing an important role in fields such as autonomous driving and logistic delivery. Our work addresses the dual challenges of training efficiency and composite optimization in path planning using Deep Reinforcement Learning (DRL). We introduce the Efficient Progressive Policy Enhancement (EPPE) framework, which integrates the advantages of sparse rewards, aimed at achieving a globally optimal policy for the agent, with process rewards that provide real-time feedback for the agent’s policy adjustment. This framework not only significantly enhances policy learning efficiency but also effectively resolves the reward coupling issues introduced by process rewards, thereby ensuring the achievement of a globally optimal policy. Within this framework, the initial reward structure incorporates guiding rewards, which are a type of process reward based on conventional path planning algorithms, and assigns significant weights to provide real-time feedback, thereby effectively enhancing the training efficiency. Additionally, the Incremental Reward Adjustment (IRA) model is proposed to progressively increase the reward weights in the composite optimization part. The Fine-tuning Policy Optimization (FPO) model, supporting the IRA model, makes gradual adjustments to the learning rate throughout the entire process. Simulated experiments demonstrate the advantage of our framework in path composite optimization. In static obstacle environments, compared to seven benchmark algorithms, the time and distance to reach the target are improved by at least 10.4%. In mixed obstacle environments, these improvements are at least 19.1% and 18.2%. Additionally, our framework also significantly enhances the training efficiency of DRL.

Oxytocin attenuates cocaine-associated place preference via the dorsal hippocampus in male and female rats

Cocaine addiction is the third largest cause of overdose-related deaths in the United States. Research investigating therapeutic targets for cocaine reward processes is key to combating this issue. The neuropeptide oxytocin (OXT) has been shown to reduce cocaine reward processes, though specific mechanisms are not understood. This study examines the effect of intra-dorsal hippocampal (DH) OXT on the expression of cocaine context associations using a conditioned place preference (CPP) paradigm. In this paradigm, one of two visually distinct chambers is paired with a drug. With repeated pairings, control animals display preference for the drug-associated context by spending more time in that context at test. In the present study, four conditioning days took place where male and female rats were injected with either cocaine or saline and placed into the corresponding chamber. On test day, rats received infusions of OXT or saline (VEH) into the DH and were allowed access to both chambers. The results show that while VEH-infused rats displayed cocaine CPP, OXT-infused rats did not prefer the cocaine-paired chamber. These findings implicate the DH as necessary in the mechanism by which OXT acts to block the expression of cocaine-context associations, providing insight into how OXT may exert its therapeutic effect in cocaine reward processes.

Prenatal exposure to alcohol and its impact on reward processing and substance use in adulthood

Heavy maternal alcohol drinking during pregnancy has been associated with altered neurodevelopment in the child but the effects of low-dose alcohol drinking are less clear and any potential safe level of alcohol use during pregnancy is not known. We evaluated the effects of prenatal alcohol on reward-related behavior and substance use in young adulthood and the potential sex differences therein. Participants were members of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort who participated in its neuroimaging follow-up in young adulthood. A total of 191 participants (28–30 years; 51% men) had complete data on prenatal exposure to alcohol, current substance use, and fMRI data from young adulthood. Maternal alcohol drinking was assessed during mid-pregnancy and pre-conception. Brain response to reward anticipation and reward feedback was measured using the Monetary Incentive Delay task and substance use in young adulthood was assessed using a self-report questionnaire. We showed that even a moderate exposure to alcohol in mid-pregnancy but not pre-conception was associated with robust effects on brain response to reward feedback (six frontal, one parietal, one temporal, and one occipital cluster) and with greater cannabis use in both men and women 30 years later. Moreover, mid-pregnancy but not pre-conception exposure to alcohol was associated with greater cannabis use in young adulthood and these effects were independent of maternal education and maternal depression during pregnancy. Further, the extent of cannabis use in the late 20 s was predicted by the brain response to reward feedback in three out of the nine prenatal alcohol-related clusters and these effects were independent of current alcohol use. Sex differences in the brain response to reward outcome emerged only during the no loss vs. loss contrast. Young adult men exposed to alcohol prenatally had significantly larger brain response to no loss vs. loss in the putamen and occipital region than women exposed to prenatal alcohol. Therefore, we conclude that even moderate exposure to alcohol prenatally has long-lasting effects on brain function during reward processing and risk of cannabis use in young adulthood.

Human ventromedial prefrontal cortex is necessary for prosocial motivation

Ventromedial prefrontal cortex (vmPFC) is vital for decision-making. Functional neuroimaging links vmPFC to processing rewards and effort, while parallel work suggests vmPFC involvement in prosocial behaviour. However, the necessity of vmPFC for these functions is unknown. Patients with rare focal vmPFC lesions (n = 25), patients with lesions elsewhere (n = 15) and healthy controls (n = 40) chose between rest and exerting effort to earn rewards for themselves or another person. vmPFC damage decreased prosociality across behavioural and computational measures. vmPFC patients earned less, discounted rewards by effort more, and exerted less force when another person benefited, compared to both control groups. Voxel-based lesion mapping revealed dissociations between vmPFC subregions. While medial damage led to antisocial behaviour, lateral damage increased prosocial behaviour relative to patients with damage elsewhere. vmPFC patients also showed reduced effort sensitivity overall, but reward sensitivity was limited to specific subregions. These results reveal multiple causal contributions of vmPFC to prosocial behaviour, effort and reward.

Common neural deficits across reward functions in major depression: a meta-analysis of fMRI studies.

Major depressive disorder (MDD) is characterized by deficient reward functions in the brain. However, existing findings on functional alterations during reward anticipation, reward processing, and learning among MDD patients are inconsistent, and it was unclear whether a common reward system implicated in multiple reward functions is altered in MDD. Here we meta-analyzed 18 past studies that compared brain reward functions between adult MDD patients (N = 477, mean age = 26.50 years, female = 59.40%) and healthy controls (N = 506, mean age = 28.11 years, females = 55.58%), and particularly examined group differences across multiple reward functions. Jack-knife sensitivity and subgroup meta-analyses were conducted to test robustness of findings across patient comorbidity, task paradigm, and reward nature. Meta-regression analyses assessed the moderating effect of patient symptom severity and anhedonia scores. We found during reward anticipation, MDD patients showed lower activities in the lateral prefrontal-thalamus circuitry. During reward processing, patients displayed reduced activities in the right striatum and prefrontal cortex, but increased activities in the left temporal cortex. During reward learning, patients showed reduced activity in the lateral prefrontal-thalamic-striatal circuitry and the right parahippocampal-occipital circuitry but higher activities in bilateral cerebellum and the left visual cortex. MDD patients showed decreased activity in the right thalamus during both reward anticipation and learning, and in the right caudate during both reward processing and learning. Larger functional changes in MDD were observed among patients with more severe symptoms and higher anhedonia levels. The thalamic-striatal circuitry functional alterations could be the key neural mechanism underlying MDD patients overarching reward function deficiencies.

Corticostriatal responses to social reward are linked to trait reward sensitivity and subclinical substance use in young adults.

Aberrant levels of reward sensitivity have been linked to substance use disorder and are characterized by alterations in reward processing in the ventral striatum (VS). Less is known about how reward sensitivity and subclinical substance use relate to striatal function during social rewards (e.g. positive peer feedback). Testing this relation is critical for predicting risk for development of substance use disorder. In this pre-registered study, participants (N = 44) underwent fMRI while completing well-matched tasks that assess neural response to reward in social and monetary domains. Contrary to our hypotheses, aberrant reward sensitivity blunted the relationship between substance use and striatal activation during receipt of rewards, regardless of domain. Moreover, exploratory whole-brain analyses showed unique relations between substance use and social rewards in temporoparietal junction. Psychophysiological interactions demonstrated that aberrant reward sensitivity is associated with increased connectivity between the VS and ventromedial prefrontal cortex during social rewards. Finally, we found that substance use was associated with decreased connectivity between the VS and dorsomedial prefrontal cortex for social rewards, independent of reward sensitivity. These findings demonstrate nuanced relations between reward sensitivity and substance use, even among those without substance use disorder, and suggest altered reward-related engagement of cortico-VS responses as potential predictors of developing disordered behavior.

The Neurochemical Anatomy of Runway Acquisition and Extinction

Abstract: A review is presented as to the neurochemical basis of the straight runway task, usually consisting of an acquisition phase followed by an extinction phase. During the acquisition of the appetitive runway task, running speeds from the start box to the goal box progressively increase over trials and then decrease when the reward is withheld. Runway extinction is susceptible to lesions of the limbic system, including the medial frontal cortex, the hippocampus, the septum, the amygdala, and the dorsomedial thalamus. When specific neurotransmitter systems are examined, extinction was delayed when noradrenaline transmission was impeded, perhaps involving noradrenergic projections to the hippocampus and neocortex. Extinction was likewise delayed after either facilitation or blocking of dopamine transmission, a result implicating an inverted U-shaped function caused by dopamine’s role in behavioral activation or reward processes. Extinction was also delayed by indirect GABAA receptor agonists injected during acquisition, explained by druginduced disinhibitory tendencies. This simple paradigm may provide information about the effects of a physiological manipulation on both cognition and emotion.

A helping HAND: therapeutic potential of MAGL inhibition against HIV-1-associated neuroinflammation.

Human immunodeficiency virus (HIV) affects nearly 40 million people globally, with roughly 80% of all people living with HIV receiving antiretroviral therapy. Antiretroviral treatment suppresses viral load in peripheral tissues but does not effectively penetrate the blood-brain barrier. Thus, viral reservoirs persist in the central nervous system and continue to produce low levels of inflammatory factors and early viral proteins, including the transactivator of transcription (Tat). HIV Tat is known to contribute to chronic neuroinflammation and synaptodendritic damage, which is associated with the development of cognitive, motor, and/or mood problems, collectively known as HIV-associated neurocognitive disorders (HAND). Cannabinoid anti-inflammatory effects are well documented, but therapeutic utility of cannabis remains limited due to its psychotropic effects, including alterations within brain regions encoding reward processing and motivation, such as the nucleus accumbens. Alternatively, inhibiting monoacylglycerol lipase (MAGL) has demonstrated therapeutic potential through interactions with the endocannabinoid system. The present study utilized a reward-related operant behavioral task to quantify motivated behavior in female Tat transgenic mice treated with vehicle or MAGL inhibitor MJN110 (1 mg/kg). Brain tissue was collected to assess dendritic injury and neuroinflammatory profiles, including dendritic microtubule-associated protein (MAP2ab) intensity, microglia density, microglia morphology, astrocyte density, astrocytic interleukin-1ß (IL-1ß) colocalization, and various lipid mediators. No significant behavioral differences were observed; however, MJN110 protected against Tat-induced dendritic injury by significantly upregulating MAP2ab intensity in the nucleus accumbens and in the infralimbic cortex of Tat(+) mice. No or only minor effects were noted for Iba-1+ microglia density and/or microglia morphology. Further, Tat increased GFAP+ astrocyte density in the infralimbic cortex and GFAP+ astrocytic IL-1ß colocalization in the nucleus accumbens, with MJN110 significantly reducing these measures in Tat(+) subjects. Lastly, selected HETE-related inflammatory lipid mediators in the striatum were downregulated by chronic MJN110 treatment. These findings demonstrate anti-inflammatory and neuroprotective properties of MJN110 without cannabimimetic behavioral effects and suggest a promising alternative to cannabis for managing neuroinflammation.