Changes In Reward Value Research Articles

Effects of psychedelic, DOI, on nucleus accumbens dopamine signaling to predictable rewards and cues in rats.

Psychedelics produce lasting therapeutic responses in neuropsychiatric diseases suggesting they may disrupt entrenched associations and catalyze learning. Here, we examine psychedelic 5-HT2A/2C agonist, DOI, effects on dopamine signaling in the nucleus accumbens (NAc) core, a region extensively linked to reward learning, motivation, and drug-seeking. We measure phasic dopamine transients following acute DOI administration in rats during well learned Pavlovian tasks in which sequential cues predict rewards. We find that DOI (0.0-1.2 mg/kg, i.p.) increases dopamine signals, photometrically measured using GRABDA optical sensor, to rewards and proximal reward cues, but not to the distal cues that predict these events. We determine that the elevated dopamine produced by DOI to reward cues occurs independently of DOI-induced changes in reward value. The increased dopamine associated with predictable reward cues and rewards supports DOI-induced increases in prediction error signaling. These findings lay a foundation for developing psychedelic strategies aimed at engaging error-driven learning mechanisms to disrupt entrenched associations or produce new associations.

유전 알고리즘을 적용한 확장된 죄수의 딜레마 게임에서 선택확률함수 조정에 따른 유효한 전략 분석

The Prisoner’s Dilemma, a representative example of game theory, is a classic game in which two players receive rewards based on two action strategies(cooperation or defection). However, many variations have been made depending onchanges in conditions(number of participants, behavioral strategies, reward values, number of games, etc.). In this study, an extended Prisoner’s Dilemma game was used in which a genetic algorithm was applied to the iterative Prisoner’sDilemma game to improve the selection probability function to determine which action strategy should be selected according to changes in reward value. A possible SPS(selection probability strategy) was developed. As a result of theprogram simulation, this SPS ranked high in the early stages, showed good performance, and was generally a dominant strategy that survived until the final stage. This study is significant in that it suggests the possibility of developing a new strategy in the Prisoner’s Dilemma game and reaffirms existing strategies that are generally effective.

Mice Exposed to Chronic low‐dose Ethanol Exhibit Reduced Sensitivity to Changes in Magnitude of Reward

While approximately 2 billion individuals consume alcohol worldwide, the majority of these individuals to not exhibit drinking patterns consistent with alcohol use disorders (AUDs). Efforts have been made in investigating and characterizing the adverse effects on learning, memory and reward seeking with individuals afflicted with AUDs in a pursuit of therapeutic advancements. However, sub‐diagnostic alcohol effects have been understudied, despite the large number of low‐dose alcohol drinkers and the potential for low dose alcohol to impact both brain and behavior.Data from our lab has shown that low‐dose alcohol exposure enhances reward motivation in male, but not female, mice, but the mechanism of this is effect is unclear. Thus, we investigated the effects of low‐dose alcohol exposure on sensitivity to change in reward magnitude. A group of adult male C57BL6J mice were trained to self‐administer a 20 ul sucrose reward and received either a low‐dose ethanol (0.5g/kg) or saline injection 1 hour after training. To assess motivation, we used a progressive ratio (PR) task in which the effort required to earn the sucrose reward was increased linearly. Mice received multiple counterbalanced PR sessions in which the progressive schedule remained the same, but the reward magnitude was changed from 20ul (baseline) to 35ul, 25ul, 15ul or 5ul in counterbalanced sessions.Consistent with sensitivity to changes in reward value, saline control mice reduced or increased responding when reward volume was reduced or increased, respectively. Similar to saline controls, chronic low‐dose ethanol exposed mice increased their responding when reward volumes were increased compared to the 20ul baseline. However, ethanol exposed mice did not reduce responding to small reductions in reward magnitude. This observation in low‐dose ethanol mice suggests either a failure to detect reductions in reward magnitude or a dissociation between reduced reward magnitude and behavioral response. This lack of strategizing behavior to maintain effort‐to‐reward balance by ethanol exposed mice may imply that chronic low‐dose ethanol exposed mice may perceive greater reward value than controls even at reduced volume and implicates even low‐dose ethanol as a contributor to aberrant reward processing.

Awareness drives changes in reward value which predict eating behavior change: Probing reinforcement learning using experience sampling from mobile mindfulness training for maladaptive eating.

Background and aimsMaladaptive eating habits are a major cause of obesity and weight-related illness. The development of empirically-based approaches, such as mindfulness training (MT) that target accurate mechanisms of action to address these behaviors is therefore critical. Two studies were conducted to examine the impact of MT on maladaptive eating and determine the involvement of reinforcement learning mechanisms underlying these effects.MethodsIn Study1, maladaptive eating behaviors were assessed using self-report questionnaires at baseline and 8 weeks after an app-based MT intervention (n = 46). A novel mindful eating craving tool was embedded in our intervention to assess: eating behaviors (intake frequency/magnitude), and reward (contentment ratings) experienced after eating. Using a well-established reinforcement learning (Rescorla-Wagner) model, expected reward values (EV) were estimated as a function of contentment levels reported after eating. In Study2 (n = 1,119), craving tool assessments were examined in an independent sample using the app in a real-world naturalistic context.ResultsStudy 1's results revealed a significant decrease in EV and eating behaviors across craving tool uses. In addition, changes in reward values predicted decreases in eating behaviors. Finally, Study 1's results revealed significant pre-post intervention reductions in self-reported eating behaviors. In Study2, we observed a significant decrease in EV, but not in eating behaviors, across craving tool uses. Study 2 also revealed a predictive relationship between EV and eating behaviors.Discussion and conclusionsThese results support the implementation of MT to prevent and treat maladaptive eating behaviors, which target reinforcement learning processes as mechanisms of action.

Altered Activity of Lateral Orbitofrontal Cortex Neurons in Mice following Chronic Intermittent Ethanol Exposure

The lateral orbitofrontal cortex (LOFC) is thought to encode information associated with consumption of rewarding substances and is essential for flexible decision-making. Indeed, firing patterns of LOFC neurons are modulated following changes in reward value associated with an action outcome relationship. Damage to the LOFC impairs behavioral flexibility in humans and is associated with suboptimal performance in reward devaluation protocols in rodents. As chronic intermittent ethanol (CIE) exposure also impairs OFC-dependent behaviors, we hypothesized that CIE exposure would alter LOFC neuronal activity during alcohol drinking, especially under conditions when the reward value of ethanol was modulated by aversive or appetitive tastants. To test this hypothesis, we monitored LOFC activity using GCaMP6f fiber photometry in mice receiving acute injections of ethanol and in those trained in operant ethanol self-administration. In naive mice, an acute injection of ethanol caused a dose-dependent decrease in the frequency but not amplitude of GCaMP6f transients. In operant studies, mice were trained on a fixed ratio one schedule of reinforcement and were then separated into CIE or Air groups. Following four cycles of CIE exposure, GCaMP6f activity was recorded during self-administration of alcohol, alcohol+quinine (aversive), or alcohol+sucrose (appetitive) solutions. LOFC neurons showed discrete patterns of activity surrounding lever presses and surrounding drinking bouts. Responding for and consumption of ethanol was greatly enhanced by CIE exposure, was aversion resistant, and was associated with signs of LOFC hyperexcitability. CIE-exposed mice also showed altered patterns of LOFC activity that varied with the ethanol solution consumed.

Effort-based decision making varies by smoking status.

A reduced willingness to perform effort based on the magnitude and probability of potential rewards has been associated with diminished dopamine function and may be relevant to chronic drug use. Here, we investigated the influence of smoking status on effort-based decisions. We hypothesized that smokers would make fewer high-effort selections than ex-smokers and never-smokers. Current smokers (n = 25), ex-smokers (≥ 1year quit, n = 23), and never-smokers (n = 19) completed the Effort Expenditure for Rewards Task in which participants select between low-effort and high-effort options to receive monetary rewards at varying levels of reward magnitude, probabilityand expected value. Overall, participants selected more high-effort options as potential reward magnitude and expected value increased. Smokers did not make fewer high-effort selections overall, but smokers were less sensitive to the changes in magnitude, probability, and expected value compared to never-smokers. Smokers were also less sensitive to the changes in probability and expected value, but not magnitude, compared to ex-smokers. Among smokers and ex-smokers, less nicotine dependence was associated with an increased likelihood of high-effort selections. These results demonstrate the relevance of smoking status to effort-based decisions and suggest that smokers have diminished sensitivity to nondrug reward value. Among ex-smokers, greater pre-existing sensitivity to reward value may have been conducive to smoking cessation, or sensitivity was improved by smoking cessation. Future prospective studies can investigate whether effort-related decision making is predictive of smoking initiation or cessation success. Willingness to perform effort to achieve a goal and sensitivity to changes in reward value are important aspects of motivation. These results showed that smokers have decreased sensitivity to changes in effort-related reward probability and expected value compared to ex-smokers and never-smokers. Potentially, improved sensitivity to rewards among ex-smokers may be a cause or consequence of smoking cessation. These findings may help explain why some smokers are able to achieve long-term abstinence.

Evidence that neuropsychological deficits following early life adversity may underlie vulnerability to depression

Early life adversity (ELA) is a risk factor for major depressive disorder (MDD), however the underlying mechanisms are not well understood. Clinical studies suggest that negative affective biases (the process, whereby cognitive processes such as learning and memory and decision-making are modified by emotional state) represent a vulnerability factor for MDD. In this study we investigate the impact of ELA on affective biases and reward-associated behaviours in rats. Sprague Dawley rat pups underwent 14 days of postnatal maternal separation (180 min/day from postnatal day 1: MS180) whilst control pups remained unhandled. In adulthood, affective biases associated with reward learning and decision-making were assessed using the affective bias test (ABT), or judgement bias task (JBT) respectively. Changes in motivation and reward sensitivity were tested in a progressive ratio (PR) schedule of operant responding and the sucrose preference test (SPT) respectively. We observed that MS180 animals expressed enhanced negative biases in response to acute corticosterone treatment but without effects on antidepressant-induced positive biases. ELA animals were impaired in their ability to develop appropriate biases in response to changes in reward value in a modified ABT but in the absence of any changes in reward sensitivity or motivation. No effects on decision-making were observed in the JBT but MS180 animals failed to develop the same more optimistic behavioural profile as controls in response to an increase in reward value. These findings suggest that ELA in rats increases vulnerability to negative affective biases and impairs animals’ ability to appropriately learn reward value, independent of a reward sensitivity or changes in motivation. These data provide important evidence linking ELA with relevant neuropsychological impairments that may explain increased risk of developing MDD.

Evidence that neuropsychological deficits following early life adversity may underlie vulnerability to depression.

Early life adversity (ELA) is a risk factor for major depressive disorder (MDD), however the underlying mechanisms are not well understood. Clinical studies suggest that negative affective biases (the process, whereby cognitive processes such as learning and memory and decision-making are modified by emotional state) represent a vulnerability factor for MDD. In this study we investigate the impact of ELA on affective biases and reward-associated behaviours in rats. Sprague Dawley rat pups underwent 14 days of postnatal maternal separation (180 min/day from postnatal day 1: MS180) whilst control pups remained unhandled. In adulthood, affective biases associated with reward learning and decision-making were assessed using the affective bias test (ABT), or judgement bias task (JBT) respectively. Changes in motivation and reward sensitivity were tested in a progressive ratio (PR) schedule of operant responding and the sucrose preference test (SPT) respectively. We observed that MS180 animals expressed enhanced negative biases in response to acute corticosterone treatment but without effects on antidepressant-induced positive biases. ELA animals were impaired in their ability to develop appropriate biases in response to changes in reward value in a modified ABT but in the absence of any changes in reward sensitivity or motivation. No effects on decision-making were observed in the JBT but MS180 animals failed to develop the same more optimistic behavioural profile as controls in response to an increase in reward value. These findings suggest that ELA in rats increases vulnerability to negative affective biases and impairs animals' ability to appropriately learn reward value, independent of a reward sensitivity or changes in motivation. These data provide important evidence linking ELA with relevant neuropsychological impairments that may explain increased risk of developing MDD.

Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation.

Disruptions to motivated behaviour are a highly prevalent and severe symptom in a number of neuropsychiatric and neurodegenerative disorders. Current treatment options for these disorders have little or no effect upon motivational impairments. We assessed the contribution of muscarinic acetylcholine receptors to motivated behaviour in mice, as a novel pharmacological target for motivational impairments. Touchscreen progressive ratio (PR) performance was facilitated by the nonselective muscarinic receptor antagonist scopolamine as well as the more subtype-selective antagonists biperiden (M1) and tropicamide (M4). However, scopolamine and tropicamide also produced increases in non-specific activity levels, whereas biperiden did not. A series of control tests suggests the effects of the mAChR antagonists were sensitive to changes in reward value and not driven by changes in satiety, motor fatigue, appetite or perseveration. Subsequently, a sub-effective dose of biperiden was able to facilitate the effects of amphetamine upon PR performance, suggesting an ability to enhance dopaminergic function. Both biperiden and scopolamine were also able to reverse a haloperidol-induced deficit in PR performance, however only biperiden was able to rescue the deficit in effort-related choice (ERC) performance. Taken together, these data suggest that the M1 mAChR may be a novel target for the pharmacological enhancement of effort exertion and consequent rescue of motivational impairments. Conversely, M4 receptors may inadvertently modulate effort exertion through regulation of general locomotor activity levels.

Macaque parvocellular mediodorsal thalamus: dissociable contributions to learning and adaptive decision‐making

Distributed brain networks govern adaptive decision‐making, new learning and rapid updating of information. However, the functional contribution of the rhesus macaque monkey parvocellular nucleus of the mediodorsal thalamus (MDpc) in these key higher cognitive processes remains unknown. This study investigated the impact of MDpc damage in cognition. Preoperatively, animals were trained on an object‐in‐place scene discrimination task that assesses rapid learning of novel information within each session. Bilateral neurotoxic (NMDA and ibotenic acid) MDpc lesions did not impair new learning unless the monkey had also sustained damage to the magnocellular division of the MD (MDmc). Contralateral unilateral MDpc and MDmc damage also impaired new learning, while selective unilateral MDmc damage produced new learning deficits that eventually resolved with repeated testing. In contrast, during food reward (satiety) devaluation, monkeys with either bilateral MDpc damage or combined MDpc and MDmc damage showed attenuated food reward preferences compared to unoperated control monkeys; the selective unilateral MDmc damage left performance intact. Our preliminary results demonstrate selective dissociable roles for the two adjacent nuclei of the primate MD, namely, MDpc, as part of a frontal cortical network, and the MDmc, as part of a frontal‐temporal cortical network, in learning, memory and the cognitive control of behavioural choices after changes in reward value. Moreover, the functional cognitive deficits produced after differing MD damage show that the different subdivisions of the MD thalamus support distributed neural networks to rapidly and fluidly incorporate task‐relevant information, in order to optimise the animals’ ability to receive rewards.

Striatal dopamine D2 receptors regulate effort but not value-based decision making and alter the dopaminergic encoding of cost.

Deficits in goal-directed motivation represent a debilitating symptom for many patients with schizophrenia. Impairments in motivation can arise from deficits in processing information about effort and or value, disrupting effective cost-benefit decision making. We have previously shown that upregulated dopamine D2 receptor expression within the striatum (D2R-OE mice) decreases goal-directed motivation. Here, we determine the behavioral and neurochemical mechanisms behind this deficit. Female D2R-OE mice were tested in several behavioral paradigms including recently developed tasks that independently assess the impact of Value or Effort manipulations on cost-benefit decision making. In vivo microdialysis was used to measure extracellular dopamine in the striatum during behavior. In a value-based choice task, D2R-OE mice show normal sensitivity to changes in reward value and used reward value to guide their actions. In an effort-based choice task, D2R-OE mice evaluate the cost of increasing the number of responses greater relative to the effort cost of longer duration responses compared to controls. This shift away from choosing to repeatedly execute a response is accompanied by a dampening of extracellular dopamine in the striatum during goal-directed behavior. In the ventral striatum, extracellular dopamine level negatively correlates with response cost in controls, but this relationship is lost in D2R-OE mice. These results show that D2R signaling in the striatum, as observed in some patients with schizophrenia, alters the relationship between effort expenditure and extracellular dopamine. This dysregulation produces motivation deficits that are specific to effort but not value-based decision making, paralleling the effort-based motivational deficits observed in schizophrenia.

Reinforcer effectiveness in dogs—The influence of quantity and quality

Reinforcer effectiveness refers to the reinforcer’s ability to control the subject’s target behaviour and is therefore critical to training success. Yet animals’ preferences, and the effectiveness of different rewards to function as reinforcers, are often assumed without scientific investigation. Here we explored the influence of reward quality, quantity and changes in reward value on motivation in domestic dogs. Subjects were trained to traverse a runway for a food reward. In Study 1, the quantity of food was varied (1 vs 5 pieces of dry food), while in Study 2, food quality was varied (1 piece of sausage vs 1 piece of dry food). Dogs were tested in two conditions (counterbalanced). In the unshifted condition, they received the low value reward in all of ten trials; in the shifted condition, reward value was altered (high value: trials 1–4 and 9–10; low value: trials 5–8). While preliminary preference tests had confirmed the relative value of the presumed high and low value rewards for both quantity and quality, dogs' responses in the runway task differed between the quality and quantity studies. Dogs ran significantly faster for the higher quality food compared to the lower quality food, confirming greater reinforcer effectiveness of the preferred food type. In contrast, there was no significant effect of food quantity on running speed at any stage. Higher quality rewards therefore appear to entail greater incentive motivation in dogs than a greater quantity of a lower value reward, with reward-specific habituation needing to be considered.

Effects of systemic cholinergic antagonism on reinforcer devaluation in macaques

The capacity to adjust actions based on new information is a vital cognitive function. An animal’s ability to adapt behavioral responses according to changes in reward value can be measured using a reinforcer devaluation task, wherein the desirability of a given object is reduced by decreasing the value of the associated food reinforcement. Elements of the neural circuits serving this ability have been studied in both rodents and nonhuman primates. Specifically, the basolateral amygdala, orbitofrontal cortex, nucleus accumbens, and mediodorsal thalamus have each been shown to play a critical role in the process of value updating, required for adaptive goal selection. As these regions receive dense cholinergic input, we investigated whether systemic injections of non-selective nicotinic or muscarinic acetylcholine receptor antagonists, mecamylamine and scopolamine, respectively, would impair performance on a reinforcer devaluation task. Here we demonstrate that in the presence of either a nicotinic or muscarinic antagonist, animals are able to shift their behavioral responses in an appropriate manner, suggesting that disruption of cholinergic neuromodulation is not sufficient to disrupt value updating, and subsequent goal selection, in rhesus macaques.

Age and sex differences in behavioral flexibility, sensitivity to reward value, and risky decision-making.

Compared with adults, adolescent behavior is often characterized by reduced behavioral flexibility, increased sensitivity to reward, and increased likelihood to take risks. These traits, which have been hypothesized to confer heightened vulnerability to psychopathologies such as substance use disorders (SUDs), have been the focus of studies in laboratory animal models that seek to understand their neural underpinnings. However, rodent studies to date have typically used only males and have adopted standard methodological practices (e.g., weight loss inducing food restriction) that are likely to have a disparate impact on adolescents compared with adults. Here, we used adolescent and adult Sprague-Dawley rats of both sexes to study instrumental behavior tasks that assess behavioral flexibility (strategy shifting and reversal learning; Experiment 1), sensitivity to reward value (outcome devaluation; Experiment 2), and risky decision making (probability discounting; Experiment 3). In Experiment 1, we found that adolescents were faster to acquire reversal learning than adults but there were no differences in strategy shifting. In Experiments 2 and 3, adolescents and adults were equally sensitive to changes in reward value and exhibited similar reductions in preference for a large reward when reinforcement probability was decreased. However, adolescents responded more efficiently and earned reinforcers at a higher rate than their same-sex, adult counterparts. Together, these findings provide only limited support for the existence of an "adolescent-typical" phenotype in Sprague-Dawley rats and instead suggest that age differences in the expression of these behaviors may depend on conditions such as pubertal status and motivational state. (PsycINFO Database Record

Reward Adaptation and the Mechanisms of Learning: Contrast Changes Reward Value in Rats and Drives Learning

Formal theories of learning suggest that associations between events are determined by the internal representations of those events. Thus, learning should depend on perceived reward value—even when perceptions differ from objective values. We examined this prediction in flavor-preference learning in rats. In two experiments, simultaneous contrast either increased perceived reward value, which was paired with a distinctive flavor cue (the positive conditioned stimulus, CS+), or decreased the perceived value of the same reward, which was then paired with a second flavor (the negative conditioned stimulus, CS–). Even though the CS+ and CS– were paired with the same objective reward, there was a preference for the CS+ in subsequent tests. Moreover, the size of contrast-produced changes in reward value during training predicted the preference for the CS+ at test. This contrast-produced learning effect illustrates the mechanisms by which associations, which normally track veridical relationships between events in the world, are formed.

Methamphetamine promotes habitual action and alters the density of striatal glutamate receptor and vesicular proteins in dorsal striatum.

Goal-directed actions are controlled by the value of the consequences they produce and so increase when what they produce is valuable and decrease when it is not. With continued invariant practice, however, goal-directed actions can become habits, controlled not by their consequences but by antecedent, reward-related states and stimuli. Here, we show that pre-exposure to methamphetamine (METH) caused abnormally rapid development of habitual control. Furthermore, these drug-induced habits differed strikingly from conventional habits; we found that they were insensitive both to changes in reward value and to the effects of negative feedback. In addition to these behavioral changes, METH exposure produced bidirectional changes to synaptic proteins in the dorsal striatum. In the dorsomedial striatum, a structure critical for goal-directed action, METH exposure was associated with a reduction in glutamate receptor and glutamate vesicular proteins, whereas in the dorsolateral striatum, a region that has previously been implicated in habit learning, there was an increase in these proteins. Together, these results indicate that METH exposure promotes habitual control of action that appears to be the result of bidirectional changes in glutamatergic transmission in the circuits underlying goal-directed and habit-based learning.

Goal-Directed and Habit-Like Modulations of Stimulus Processing during Reinforcement Learning.

Recent research has shown that perceptual processing of stimuli previously associated with high-value rewards is automatically prioritized even when rewards are no longer available. It has been hypothesized that such reward-related modulation of stimulus salience is conceptually similar to an "attentional habit." Recording event-related potentials in humans during a reinforcement learning task, we show strong evidence in favor of this hypothesis. Resistance to outcome devaluation (the defining feature of a habit) was shown by the stimulus-locked P1 component, reflecting activity in the extrastriate visual cortex. Analysis at longer latencies revealed a positive component (corresponding to the P3b, from 550-700 ms) sensitive to outcome devaluation. Therefore, distinct spatiotemporal patterns of brain activity were observed corresponding to habitual and goal-directed processes. These results demonstrate that reinforcement learning engages both attentional habits and goal-directed processes in parallel. Consequences for brain and computational models of reinforcement learning are discussed.SIGNIFICANCE STATEMENT The human attentional network adapts to detect stimuli that predict important rewards. A recent hypothesis suggests that the visual cortex automatically prioritizes reward-related stimuli, driven by cached representations of reward value; that is, stimulus-response habits. Alternatively, the neural system may track the current value of the predicted outcome. Our results demonstrate for the first time that visual cortex activity is increased for reward-related stimuli even when the rewarding event is temporarily devalued. In contrast, longer-latency brain activity was specifically sensitive to transient changes in reward value. Therefore, we show that both habit-like attention and goal-directed processes occur in the same learning episode at different latencies. This result has important consequences for computational models of reinforcement learning.

Intermittent feeding alters sensitivity to changes in reward value

The influence of binge-like feeding schedules on subsequent food-related behavior is not well understood. We investigated the effect of repeated cycles of restriction and refeeding on two food-related behaviors; goal-directed responding for a palatable food reward and sensory-specific satiety. Hungry rats were trained to perform two instrumental actions for two distinct food outcomes and were then subjected to repeated cycles of restricted and unrestricted access to their maintenance chow for 30-days or were maintained on food restriction. Goal-directed control was then assessed using specific satiety-induced outcome devaluation. Rats were given 1 h access to one of theoutcomes and were then immediately given a choice between the two actions. Rats maintained on restriction responded more for the valued than the devalued reward but rats with a history of restriction and refeeding failed to show this effect. Importantly, all rats showed sensory-specific satiety when offered a choice between the two foods, indicating that pre-feeding selectively reduced the value of the pre-fed food. By contrast, sensory-specific satiety was not observed in rats with a history of intermittent feeding when the foods were offered sequentially. These results indicate that, similar to calorically dense diets, intermittent feeding patterns can impair the performance of goal-directed actions as well as the ability to reject a pre-fed food when it is offered alone.

Abstract # 1780 Deconstructing cancer-related fatigue: A role for motivational deficits

Cancer-related fatigue is a common, debilitating condition which is proposed to be associated with inflammatory mechanisms. The objective of our ongoing project is to objectively assess incentive motivation in cancer-related fatigue and its association with inflammation. Patients recruited at MD Anderson Cancer Center were tested for incentive motivation using a validated computerized task, the Effort Expenditure for Rewards Task (EEfRT). A blood sample was obtained on the same day. In a preliminary sample of 29 subjects, 15 patients with high fatigue and 14 patients with low fatigue were identified. Compared to low fatigued patients, patients with high fatigue showed an increased willingness to exert effort, reflected in overall higher percentage of high effort choices on the EEfRT (43% vs. 25%, p = .03). Whereas low fatigued patients were sensitive to changes in reward value, reflected in more high effort choices when rewards for high effort were increased (low vs. medium reward: 14% vs. 24%, p = .03; medium vs. high reward: 24% vs. 36%, p = .01), patients with high fatigue did not show this sensitivity (low vs. medium: 38% vs. 44%, p = .07; medium vs. high: 44 vs. 51%, p = .27). In conclusion, patients with high fatigue overall make high effort choices, regardless of the outcome-value of the invested effort. Markers of inflammation assessed in serum will be determined at completion of the study.

Decreasing Striatopallidal Pathway Function Enhances Motivation by Energizing the Initiation of Goal-Directed Action.

Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OEdev mice) are reversed by decreasing function of the striatopallidal "no-go" pathway. To this end, we expressed the Gαi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO). Using a head-mounted miniature microscope we confirmed with calcium imaging in awake mice that hM4D activation by CNO inhibits striatopallidal function measured as disinhibited downstream activity in the globus pallidus. Mice were then tested in three operant tasks that address motivated behavior, the progressive ratio task, the progressive hold-down task, and outcome devaluation. Decreasing striatopallidal function in the dorsomedial striatum or nucleus accumbens core enhanced motivation in D2R-OEdev mice and control littermates. This effect was due to increased response initiation but came at the cost of goal-directed efficiency. Moreover, response vigor and the sensitivity to changes in reward value were not altered. Chronic activation of hM4D by administering CNO for 2 weeks in drinking water did not affect motivation due to a tolerance effect. However, the acute effect of CNO on motivation was reinstated after discontinuing chronic treatment for 48 h. Used as a therapeutic approach, striatopallidal inhibition should consider the risk of impairing goal-directed efficiency and behavioral desensitization. Motivation involves a directional component that allows subjects to efficiently select the behavior that will lead to an optimal outcome and an activational component that initiates and maintains the vigor and persistence of actions. Striatal output pathways modulate motivated behavior, but it remains unknown how these pathways regulate specific components of motivation. Here, we found that the indirect pathway controls response initiation without affecting response vigor or the sensitivity to changes in the reward outcome. A specific enhancement in the activational component of motivation, however, can come at the cost of goal-directed efficiency when a sustained response is required to obtain the goal. These data should inform treatment strategies for brain disorders with impaired motivation such as schizophrenia and Parkinson's disease.