Reward Seeking Research Articles

Orbitofrontal intronic circular RNA from Nrxn3 mediates reward learning and motivation for reward

The orbitofrontal cortex (OFC) is a vital component of brain reward circuitry that is important for reward seeking behavior. However, OFC-mediated molecular mechanisms underlying rewarding behavior are understudied. Here, we report the first circular RNA (circRNA) profile associated with appetitive reward and identify regulation of 92 OFC circRNAs by sucrose self-administration. Among these changes, we observed downregulation of circNrxn3, a circRNA originating from neurexin 3 (Nrxn3), a gene involved in synaptogenesis, learning, and memory. Transcriptomic profiling via RNA sequencing and qPCR of the OFC following in vivo knock-down of circNrxn3 revealed differential regulation of genes associated with pathways important for learning and memory and altered splicing of Nrxn3. Furthermore, circNrxn3 knock-down enhanced sucrose self-administration and motivation for sucrose. Using RNA-immunoprecipitation, we report binding of circNrxn3 to the known Nrxn3 splicing factor SAM68. circNrxn3 is the first reported circRNA capable of regulating reward behavior and circNrxn3-mediated interactions with SAM68 may impact subsequent downstream processing of RNAs such as the regulation of gene expression and splicing.

Sex and individual differences in the effect of chronic low-dose ethanol on behavioral strategy selection.

The development of an alcohol use disorder (AUD) involves impaired behavioral control and flexibility. Behavioral inflexibility includes an inability to shift behavior in response to changes in behavioral outcomes. Low levels of ethanol drinking may promote the formation of inflexible, habitual reward seeking, but this may depend on the timing of ethanol exposure in relation to learning. The goal of this study was to determine whether a history of low-dose ethanol exposure promoted contingency-insensitive sucrose seeking and altered behavioral strategy selection. Male and female C57BL/6J mice were trained to perform a response (lever press) for sucrose on two different reinforcement schedules: one that is thought to promote inflexible responding (random interval) and one that maintains flexible responding (variable ratio [VR]). Following instrumental training each day, mice were exposed to saline or low-dose ethanol (0.5 g/kg; i.p.) either proximal (1 h after) or distal (4 h after) to learning. Mice were then tested for sensitivity to changes in contingency in a contingency degradation test. A history of low-dose ethanol exposure shifted behavioral strategy selection, as measured by reward tracking behavior, but this depended on sex and reinforcement schedule history. Both male and female mice used different strategies depending on the reinforcement schedule, but only males exhibited ethanol-induced shifts in strategy selection. A history of low-dose ethanol exposure did not impact contingency sensitivity in males but promoted insensitivity in females specifically on the VR lever. Female mice show distinct behavioral effects of repeated, low-dose ethanol exposure as compared to males, with sex differences in the use of reward tracking strategies to guide behavior. Future studies should investigate sex differences in the neural consequences of chronic low-dose ethanol exposure that may underlie behavioral changes.

Dopaminergic systems create reward seeking despite adverse consequences

Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking1. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking2,3, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals.

Fentanyl-induced reward seeking is sex and dose dependent and is prevented by D-cysteine ethylester.

Introduction: Despite their inclination to induce tolerance, addictive states, and respiratory depression, synthetic opioids are among the most effective clinically administered drugs to treat severe acute/chronic pain and induce surgical anesthesia. Current medical interventions for opioid-induced respiratory depression (OIRD), wooden chest syndrome, and opioid use disorder (OUD) show limited efficacy and are marked by low success in the face of highly potent synthetic opioids such as fentanyl. D-Cysteine ethylester (D-CYSee) prevents OIRD and post-treatment withdrawal in male/female rats and mice with minimal effect on analgesic status. However, the potential aversive or rewarding effects of D-CYSee have yet to be fully characterized and its efficacy could be compromised by interactions with opioid-reward pathology. Methods: Using a model of fentanyl-induced conditioned place preference (CPP), this study evaluated 1) the dose and sex dependent effects of fentanyl to induce rewarding states, and 2) the extent to which D-CYSee alters affective state and the acquisition of fentanyl-induced seeking behaviors. Results: Fentanyl reward-related effects were found to be dose and sex dependent. Male rats exhibited a range-bound dose response centered at 5µg/kg. Female rats exhibited a CPP only at 50µg/kg. This dose was effective in 25% of females with the remaining 75% showing no significant CPP at any dose. Pretreatment with 100mg/kg, but not 10mg/kg, D-CYSee prevented acquisition of fentanyl seeking in males while both doses were effective at preventing acquisition in females. Discussion: These findings suggest that D-CYSee is an effective co-treatment with prescribed opioids to reduce the development of OUD.

How Sucrose Preference Is Gained and Lost: An In-Depth Analysis of Drinking Behavior during the Sucrose Preference Test in Mice.

The sucrose preference test (SPT) is a widely used preclinical assay for studying stress-sensitive reward behaviors and antidepressant treatments in rodents, with some face, construct, and predictive validity. However, while stress-induced loss of sucrose preference is presumed to reflect an anhedonic-like state, little detail is known about what behavioral components may influence performance in the SPT in stress-naive or stressed rodents. We analyzed the licking microstructure of mice during the SPT to evaluate how preference is expressed and lost following chronic stress. In stress-naive mice, preference is expressed as both longer and more numerous drinking bouts at the sucrose bottle, compared with the water bottle. We also found evidence that memory of the sucrose bottle location supports preference. Through manipulations of the caloric content of the sweetener or caloric need of the mouse, we found that energy demands and satiety signals do not affect either preference or the underlying drinking behavior. Both acute and chronic stress impaired sucrose location memory and reduced the number of drinking bouts at the sucrose bottle, the latter of which explained the loss of sucrose preference in stress susceptible mice compared with stress resilient mice. Female mice generally exhibited similar drinking behavior to male mice but may be less susceptible to chronic stress and display better memory performance than male mice, both before and after chronic stress. Our data suggest that chronic stress inhibits a sucrose preference by reducing reward seeking behavior without affecting palatability.

Kappa opioid receptor agonist U50,488 inhibits dopamine more in caudal than rostral nucleus accumbens core.

The nucleus accumbens (NAc) core is involved in regulating stress and shaping reward seeking behaviours. Multiple neuromodulators, including dynorphin/kappa opioid receptor (KOR) and dopamine systems, converge in this area to influence behavioural outcomes. KOR activation acutely inhibits dopamine release and chronically depresses overall dopamine transmission. Recently, studies in the NAc shell have revealed that the impact of KOR activation on behaviour is regionally specific, and these rostro-caudal differences are likely driven by greater control of KORs over dopamine inhibition in the caudal compared with rostral subregion. Given the importance of NAc core, particularly the interaction between KORs and dopamine in regulating reward seeking behaviours, we examined the impact of KOR activation on dopamine release and uptake along the rostro-caudal axis in the NAc core of male and female mice. Using ex vivo fast scan cyclic voltammetry, we observed that KOR mediated inhibition of dopamine release was significantly greater in caudal compared with rostral NAc core with no significant sex differences observed. These data suggest that KORs regulate dopamine release differentially along the rostro-caudal axis, providing a new axis on which to examine the process by which the KOR/dopamine system controls reward encoding.

Unpredictable, intermittent access to sucrose or water promotes increased reward pursuit in rats

Reward uncertainty can sensitize reward pathways, promoting increased reward-seeking and -taking behaviours. This is relevant to human conditions such as pathological gambling, eating disorders and drug addiction. In the context of addiction, preclinical self-administration procedures have been developed to model the intermittency of human drug use. These intermittent-access (IntA) procedures involve intermittent but predictable access to drug during self-administration sessions. However, human drug use typically involves intermittent and unpredictable drug access. We introduce a new procedure modeling unpredictable, intermittent access (UIntA) to a reinforcer, and we compare it to procedures that provide predictable reinforcer availability; continuous (ContA) or intermittent (IntA) access. Female rats self-administered water or liquid sucrose in daily hour-long sessions. IntA and ContA rats had access to a fixed volume of water or sucrose (0.1 ml), under a fixed ratio 3 schedule of reinforcement. IntA rats had predictable 5-min reinforcer ON and 25-min reinforcer OFF periods. ContA rats had 60 min of reinforcer access during each session. For UIntA rats, variation in the length of ON and OFF periods (1, 5 or 9 min/period), response requirement (variable ratio 3 schedule of reinforcement), reinforcer probability (50%) and quantity (0, 0.1 or 0.2 ml) introduced reward uncertainty. Following 14 daily self-administration sessions, UIntA rats showed the highest levels of responding for water or sucrose under progressive ratio conditions, responding under extinction conditions, and cue-induced reinstatement of sucrose seeking. Thus, unpredictable, intermittent reward access promotes increased reward pursuit. This has implications for modeling addiction and other disorders of increased reward seeking.

Arky neurons and reward seeking.

Arky neurons and reward seeking.

Hormone sensitivity predicts the beneficial effects of transdermal estradiol on reward-seeking behaviors in perimenopausal women: A randomized controlled trial

Depression is highly prevalent during the menopause transition (perimenopause), and often presents with anxious and anhedonic features. This increased vulnerability for mood symptoms is likely driven in part by the dramatic hormonal changes that are characteristic of the menopause transition, as prior research has linked fluctuations in estradiol (E2) to emergence of depressed mood in at risk perimenopausal women. Transdermal estradiol (TE2) has been shown to reduce the severity of depression in clinically symptomatic women, particularly in those with recent stressful life events. This research extends prior work by examining the relation between E2 and reward seeking behaviors, a precise behavioral indicator of depression. Specifically, the current study utilizes a randomized, double blind, placebo-controlled design to investigate whether mood sensitivity to E2 flux (“hormone sensitivity”) predicts the beneficial effects of TE2 interventions on reward seeking behaviors in perimenopausal women, and whether recent stressful life events moderate any observed associations. MethodParticipants were 66 women who met standardized criteria for being early or late perimenopausal based on bleeding patterns. Participants were recruited from a community sample; therefore, mood symptoms varied across the continuum and the majority of participants did not meet diagnostic criteria for a depressive or anxiety disorder at the time of enrollment. Hormone sensitivity was quantified over an 8-week baseline period, using within-subjects correlations between repeated weekly measures of E2 serum concentrations and weekly anxiety (State Trait Anxiety Inventory) and anhedonia ratings (Snaith-Hamilton Pleasure Scale). Women were then randomized to receive 8 weeks of TE2 (0.1 mg) or transdermal placebo, and reward-seeking behaviors were assessed using the Effort-Expenditure for Rewards Task (EEfRT). ResultsParticipants who were randomized to receive transdermal estradiol and who demonstrated greater anxiety sensitivity to E2 fluctuations at baseline, demonstrated more reward seeking behaviors on the EEfRT task. Notably, the strength of the association between E2-anxiety sensitivity and post-randomization EEfRT for TE2 participants increased when women experienced more recent stressful life events and rated those events as more stressful. E2-anhedonia sensitivity was not associated with reward-seeking behaviors. ConclusionPerimenopausal women who are more sensitive to E2 fluctuations and experienced more recent life stress may experience a greater benefit of TE2 as evidenced by an increase in reward seeking behaviors.

Effects of adolescent ethanol exposure on adult nondrug reward seeking behavior in male and female mice.

Adolescent alcohol use is associated with an increased likelihood of developing an alcohol use disorder in adulthood, potentially due to the effects of alcohol exposure on reward-seeking behavior. However, it remains unclear whether adolescent drinking is sufficient to alter nondrug reward seeking in adulthood. As adolescence is a period of both brain and sexual maturation, which occur in a sex-dependent manner, males and females may be differentially sensitive to the consequences of adolescent alcohol exposure. The present study investigated whether adolescent ethanol exposure affected food reward taking and seeking in male and female adult mice. Male and female C57BL/6J mice underwent intermittent ethanol exposure (AIE) via vapor inhalation during early adolescence (28-42 days of age). At 10 weeks of age, the mice were trained in a conditioned place preference paradigm (CPP) for a food reward. We measured food consumption, CPP, and cFos expression in multiple brain regions following CPP testing. Data were analyzed using repeated measures analysis of variance with exposure (air vs. AIE), sex, and time as factors. AIE exposure increased food consumption during CPP training in adult male mice, but reduced pellet consumption in adult female mice. AIE exposure impaired CPP expression only in female mice. Despite these behavioral differences, exposure to the reward-paired chamber did not induce differential cFos expression following CPP testing in the prelimbic and infralimbic cortices or the nucleus accumbens core and shell. These findings indicate that adolescent ethanol exposure disrupted nondrug reward taking and seeking in adulthood in female mice and altered consumption in adult male mice.

Differential Modulation of GABAergic and Glutamatergic Neurons in the Ventral Pallidum by GABA and Neuropeptides.

The ventral pallidum (VP) is an integral locus in the reward circuitry and a major target of GABAergic innervation of both D1-medium spiny neurons (MSNs) and D2-MSNs from the nucleus accumbens. The VP contains populations of GABAergic [VPGABA, GAD2(+), or VGluT(-)] and glutamatergic [VPGlutamate, GAD2(-), or VGluT(+)] cells that facilitate positive reinforcement and behavioral avoidance, respectively. MSN efferents to the VP exert opponent control over behavioral reinforcement with activation of D1-MSN afferents promoting and D2-MSN afferents inhibiting reward seeking. How this afferent-specific and cell type-specific control of reward seeking is integrated remains largely unknown. In addition to GABA, D1-MSNs corelease substance P to stimulate neurokinin 1 receptors (NK1Rs) and D2-MSNs corelease enkephalin to activate μ-opioid receptors (MORs) and δ-opioid receptors. These neuropeptides act in the VP to alter appetitive behavior and reward seeking. Using a combination of optogenetics and patch-clamp electrophysiology in mice, we found that GAD2(-) cells receive weaker GABA input from D1-MSN, but GAD2(+) cells receive comparable GABAergic input from both afferent types. Pharmacological activation of MORs induced an equally strong presynaptic inhibition of GABA and glutamate transmission on both cell types. Interestingly, MOR activation hyperpolarized VPGABA but not VGluT(+). NK1R activation inhibited glutamatergic transmission only on VGluT(+) cells. Our results indicate that the afferent-specific release of GABA and neuropeptides from D1-MSNs and D2-MSNs can differentially influence VP neuronal subtypes.

Ventral Pallidal GABAergic Neuron Calcium Activity Encodes Cue-Driven Reward Seeking and Persists in the Absence of Reward Delivery.

Reward-seeking behavior is often initiated by environmental cues that signal reward availability. This is a necessary behavioral response; however, cue reactivity and reward-seeking behavior can become maladaptive. To better understand how cue-elicited reward seeking becomes maladaptive, it is important to understand the neural circuits involved in assigning appetitive value to rewarding cues and actions. Ventral pallidum (VP) neurons are known to contribute to cue-elicited reward-seeking behavior and have heterogeneous responses in a discriminative stimulus (DS) task. The VP neuronal subtypes and output pathways that encode distinct aspects of the DS task remain unknown. Here, we used an intersectional viral approach with fiber photometry to record bulk calcium activity in VP GABAergic (VP GABA) neurons in male and female rats as they learned and performed the DS task. We found that VP GABA neurons are excited by reward-predictive cues but not neutral cues and that this response develops over time. We also found that this cue-evoked response predicts reward-seeking behavior and that inhibiting this VP GABA activity during cue presentation decreases reward-seeking behavior. Additionally, we found increased VP GABA calcium activity at the time of expected reward delivery, which occurred even on trials when reward was omitted. Together, these findings suggest that VP GABA neurons encode reward expectation, and calcium activity in these neurons encodes the vigor of cue-elicited reward seeking.SIGNIFICANCE STATEMENT VP circuitry is a major driver of cue-evoked behaviors. Previous work has found that VP neurons have heterogenous responses and contributions to reward-seeking behavior. This functional heterogeneity is because of differences of neurochemical subtypes and projections of VP neurons. Understanding the heterogenous responses among and within VP neuronal cell types is a necessary step in further understanding how cue-evoked behavior becomes maladaptive. Our work explores the canonical GABAergic VP neuron and how the calcium activity of these cells encodes components of cue-evoked reward seeking, including the vigor and persistence of reward seeking.

Astrocyte Regulation of Stress- and Ethanol Dependence-Induced Changes in Reward Seeking

Astrocyte Regulation of Stress- and Ethanol Dependence-Induced Changes in Reward Seeking

A comprehensive assay of social motivation reveals sex-specific roles of autism-associated genes and oxytocin

Social motivation is critical to the development of typical social functioning. Social motivation, specifically one or more of its components (e.g., social reward seeking or social orienting), could be relevant for understanding phenotypes related to autism. We developed a social operant conditioning task to quantify effort to access a social partner and concurrent social orienting in mice. We established that mice will work for access to a social partner, identified sex differences, and observed high test-retest reliability. We then benchmarked the method with two test-case manipulations. Shank3B mutants exhibited reduced social orienting and failed to show social reward seeking. Oxytocin receptor antagonism decreased social motivation, consistent with its role in social reward circuitry. Overall, we believe that this method provides a valuable addition to the assessment of social phenotypes in rodent models of autism and the mapping of potentially sex-specific social motivation neural circuits.

Decreased Ventral Tegmental Area CB1R Signaling Reduces Sign Tracking and Shifts Cue-Outcome Dynamics in Rat Nucleus Accumbens.

Sign-tracking (ST) rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug seeking compared with goal-tracking or intermediate rats. Cue-evoked dopamine in the nucleus accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system, endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the ventral tegmental area (VTA) to control cue-evoked striatal dopamine levels. We use cell type-specific optogenetics, intra-VTA pharmacology, and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign tracking. We trained male and female rats in a Pavlovian lever autoshaping (PLA) task to determine their tracking groups before testing the effect of VTA → NAc dopamine inhibition. We found that this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase food cup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from a dopamine sensor, GRABDA (AAV9-hSyn-DA2m), we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping in female rats. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases in NAc shell, but not core, dopamine levels during reward delivery [unconditioned stimulus (US)]. Our results suggest that CB1R signaling in the VTA influences the balance between the conditioned stimulus-evoked and US-evoked dopamine responses in the NAc shell and biases behavioral responding to cues in sign-tracking rats.SIGNIFICANCE STATEMENT Substance use disorder (SUD) is a chronically relapsing psychological disorder that affects a subset of individuals who engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences before drug experience that predict SUD and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug-motivated behaviors.

A History of Low-Dose Ethanol Shifts the Role of Ventral Hippocampus during Reward Seeking in Male Mice.

Although casual drinkers are a majority of the alcohol drinking population, understanding of the long-term effects of chronic exposure to lower levels of alcohol is limited. Chronic exposure to lower doses of ethanol may facilitate the development of alcohol use disorders, potentially because of ethanol effects on reward learning and motivation. Indeed, our previously published findings showed that chronic low-dose ethanol exposure enhanced motivation for sucrose in male, but not female, mice. As the ventral hippocampus (vHPC) is sensitive to disruption by higher doses of chronic ethanol and tracks reward-related information, we hypothesized that this region is impacted by low-dose ethanol and, further, that manipulating vHPC activity would alter reward motivation. In vivo electrophysiological recordings of vHPC population neural activity during progressive ratio testing revealed that vHPC activity was suppressed in the period immediately after reward seeking (lever press) in ethanol-naive controls, whereas suppression of vHPC activity anticipated reward seeking in ethanol-exposed mice. In both ethanol-naive and exposed mice, vHPC activity was suppressed before a reward magazine entry. Temporally selective inhibition of vHPC using optogenetics increased motivation for sucrose in ethanol-naive controls, but not in ethanol-exposed mice. Further, regardless of exposure history, vHPC inhibition promoted checking of the reward magazine, indicating a role for vHPC in reward tracking. There was no effect of chemogenetic inhibition of the vHPC either during training or testing on sucrose reward motivation. These results reveal novel ethanol-induced alterations in vHPC neural activity that shift how vHPC activity is able to regulate reward seeking.

Measuring Motivation Using the Progressive Ratio Task in Adolescent Mice.

Alterations in reward seeking are a hallmark of multiple psychiatric disorders, including substance abuse and depression. One important aspect of reward seeking is 'wanting', which can be operationalized in both humans and rodents in tasks such as the progressive ratio, in which an increasing amount of work is required to earn a given reward. Importantly, many disorders with reward-seeking deficits are believed to have an important neurodevelopmental component, underscoring the importance of being able to study changes in motivation across the lifespan. Although this task has been adapted for both adult and adolescent rats, in mice it has predominantly been used to assay motivational changes in adults. Specific concerns in adapting this task from adult to adolescent mice include (1) optimizing a food restriction paradigm suitable for growing animals whose weights are naturally dynamically changing and (2) identifying task conditions that allow younger, smaller mice to perform the task while minimizing the length of the behavioral shaping required to measure motivation at specific developmental dates. Toward that end, we now report a protocol for appropriate weight management in developing animals that require food restriction, and a protocol for behavioral shaping and progressive ratio testing in adolescent mice, including an assessment of whether the animals perform better with lever presses or nose pokes as the required operant response. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Food restriction and weight management in the context of developing mice Alternate Protocol: Food restriction and weight management of developing mice without projected growth chart: Utilization of baseline mice Basic Protocol 2: Operant box design, progressive ratio training, testing, and data analysis in adolescent mice.

From Prediction to Action: Dissociable Roles of Ventral Tegmental Area and Substantia Nigra Dopamine Neurons in Instrumental Reinforcement.

Reward seeking requires the coordination of motor programs to achieve goals. Midbrain dopamine neurons are critical for reinforcement, and their activation is sufficient for learning about cues, actions, and outcomes. Here we examine in detail the mechanisms underlying the ability of ventral tegmental area (VTA) and substantia nigra (SNc) dopamine neurons to support instrumental learning. By exploiting numerous behavioral tasks in combination with time-limited optogenetic manipulations in male and female rats, we reveal that VTA and SNc dopamine neurons generate reinforcement through separable psychological processes. VTA dopamine neurons imbue actions and their associated cues with motivational value that allows flexible and persistent pursuit, whereas SNc dopamine neurons support time-limited, precise, action-specific learning that is nonscalable and inflexible. This architecture is reminiscent of actor-critic reinforcement learning models with VTA and SNc instructing the critic and actor, respectively. Our findings indicate that heterogeneous dopamine systems support unique forms of instrumental learning that ultimately result in disparate reward-seeking strategies.SIGNIFICANCE STATEMENT Dopamine neurons in the midbrain are essential for learning, motivation, and movement. Here we describe in detail the ability of VTA and SNc dopamine neurons to generate instrumental reinforcement, a process where an agent learns about actions they can emit to earn reward. While rats will avidly work and learn to respond for activation of VTA and SNc dopamine neurons, we find that only VTA dopamine neurons imbue actions and their associated cues with motivational value that spur continued pursuit of reward. Our data support a hypothesis that VTA and SNc dopamine neurons engage distinct psychological processes that have consequences for our understanding of these neurons in health and disease.

Neural Mechanisms of the Reward System and the Cognitive Control System in Internet Addicts

As a behavioral addiction, Internet addiction has become a global problem that seriously affects people’s mental health. According to the neurobiological model of brain development, revealing the neural mechanisms of reward and the cognitive control system of Internet addicts is the key to solving internet addiction. The key to the problem of addiction is also a major issue in psychological research. Behavioral research has explored the characteristics of high reward seeking and low cognitive control in Internet addiction; research on neural mechanisms has revealed that the deficits in reward and cognitive control systems are the root of this behavior. Comparative studies with drug addiction have found that Internet addiction has a unique reward mechanism. These studies have deepened the understanding of the psychological and neural mechanisms of Internet addiction, but there are still differences in the screening and inclusion criteria for Internet addiction. There are some problems that need to be solved urgently, such as science, general classification, lack of causal research, controversial intervention and treatment effects, and loopholes in research paradigms.

How Obstructed Action Efficacy Impacts Reward-Based Decision Making in Adolescent Depression: An fMRI Study

Disruption of reward seeking behavior by unforeseen obstacles can promote negative affect, including frustration and irritability, in adolescents. Repeated experiences of obstructed reward may in fact contribute to the development of depression in adolescents. However, the neurocognitive mechanisms whereby goal disruption impacts reward processing in adolescent depression have not yet been characterized. The present study addresses this gap using neuroimaging and a novel paradigm to assess how incidental action obstruction impacts reward-based decision-making. We assessed 62 unmedicated adolescents with Major Depressive Disorder (MDD; mean age=15.6, SD=1.4, 67% female participants) and 68 matched healthy control participants (mean age=15.3, SD=1.4, 50% female participants) using functional magnetic resonance imaging (fMRI) while they played a card game in which they had to guess between two options to earn points, in low- and high-stake conditions. Functioning of button presses through which they made decisions was intermittently blocked, thereby blocking action efficacy. Participants with MDD made fewer button press repetitions in response to action efficacy obstruction, which was more apparent in the low-stake condition (Rate Ratio =0.85, p=0.034). During response repetition across stake conditions, MDDs exhibited higher activation in regions in the ventromedial prefrontal cortex, caudate, and putamen (F(1,125)= 16.4-25.6, df=1,125; ps<0.001; Hedges' g=0.85-0.98). Adolescent with depression tend to exhibit less flexible behavioral orientation in the face of blocked action efficacy, and abnormalities in neural systems critical to regulating negative affect during reward-based decision-making. This research highlights possible mechanisms relevant to understanding and treating affective dysregulation in adolescent depression.