Progressive Ratio Task Research Articles

Dopamine D1 receptors in the medial orbitofrontal cortex support effort-related responding in rats

Rodent studies on effort-related responding provide a tool to analyze basal aspects of motivation and to model psychiatric motivational dysfunctions reflecting low exertion of effort or reduced behavioral activation. It turned out that dopamine (DA) signaling in brain areas such as nucleus accumbens are essential in regulating effort-related motivational function and could play a major role in motivational dysfunction in psychiatric disorders. Recent rodent studies revealed that the medial orbitofrontal cortex (mOFC) is another key component of the neural circuitry regulating effort-related motivational function. The mOFC receives prominent DA input, however, the behavioral role of mOFC DA signaling is unknown. Here, we investigated whether DA signaling in the mOFC supports effort-related responding in rats. Results demonstrate that an intra-mOFC D1 receptor blockade markedly reduced effort-related responding in a progressive ratio task. Notably, the magnitude of this effect was comparable to the one caused by a systemic DA depletion induced by the VMAT-2 inhibitor tetrabenazine or by a satiety-induced motivational downshift. Collectively, our data show for the first time that D1 receptor activity in the mOFC plays a critical role in high effort responding. These results support findings in humans pointing to a role of the mOFC in effort-related responding. It is well known that the mOFC becomes dysfunctional in depression and schizophrenia. Our data point to the possibility that reduced mOFC DA activity could contribute to effort-related motivational symptoms in these disorders and support the notion that the DA system may be a drug target to treat effort-related motivational symptoms.

A neurobiological correlate of stress-induced nicotine-seeking behavior among cigarette smokers.

Stress is known to influence smoking relapse. Experimental studies indicate that acute stress increases nicotine-seeking behavior, yet neurobiological mechanisms remain poorly understood. Herein, we investigated disrupted excitatory neural activity in the dorsolateral prefrontal cortex (dlPFC) as a mechanism of stress-induced nicotine-seeking behavior. Non-treatment-seeking cigarette smokers were screened for psychiatric, medical, and neuroimaging contraindications. Using a double-blind, placebo-controlled, randomized crossover design, participants (N=21) completed two oral-dosing sessions: stress (yohimbine 54mg+hydrocortisone 10mg) vs placebo (lactose 54mg+lactose 10mg). During each experimental session, working memory proficiency, dlPFC excitatory neural activity, nicotine-seeking behavior, and subjective effects were measured. dlPFC excitatory neural activity was quantified via glutamate modulation during working memory performance using functional proton magnetic resonance spectroscopy. Nicotine-seeking behavior was assayed using a cigarette puffs vs money choice progressive ratio task. Results indicated that yohimbine + hydrocortisone evoked a sustained physiological stress response (elevated heart rate, blood pressure, saliva cortisol, and saliva α-amylase levels; ps<.05). Relative to placebo levels, acute stress increased nicotine-seeking behavior (ps<.05), disrupted dlPFC glutamate modulation (p=.025), and impaired dlPFC function (working memory proficiency; ps<.05). The stress-induced increase in nicotine-seeking behavior was linearly related to the stress-induced disruption of dlPFC glutamate modulation (R2 =0.24-0.37; ps<.05). These findings suggest that disrupted dlPFC excitatory neural activity is a neurobiological correlate of acute stress-induced nicotine-seeking behavior. These findings further emphasize the central role of the dlPFC in regulating drug-seeking behavior. Future studies are needed to evaluate interventions to improve dlPFC resilience to acute stress effects, including neurostimulation, working memory training, and "anti-stress" medications.

A Touchscreen Motivation Assessment Evaluated in Huntington's Disease Patients and R6/1 Model Mice.

Apathy is pervasive across many neuropsychiatric disorders but is poorly characterized mechanistically, so targeted therapeutic interventions remain elusive. A key impediment has been the lack of validated assessment tools to facilitate translation of promising findings between preclinical disease models and patients. Apathy is a common symptom in Huntington's disease. Due to its established genetic basis and the availability of defined animal models, this disease offers a robust translational framework for linking motivated behavior with underlying neurobiology and an ideal context in which to evaluate a quantitative, translational apathy assessment method. In this study we therefore aimed to demonstrate the validity of using touchscreen-delivered progressive ratio tasks to mirror apathy assessment in Huntington's disease patients and a representative mouse model. To do this we evaluated Huntington's disease patients (n = 23) and age-matched healthy controls (n = 20), and male R6/1 mice (n = 23) and wildtype controls (n = 29) for apathy-like behavior using touchscreen-delivered progressive ratio tasks. The primary outcome measure of the assessment was breakpoint, defined as the highest number of touchscreen responses emitted before task engagement ceased. Patients and R6/1 mice were both found to exhibit significantly reduced breakpoints relative to their respective control groups, consistent with apathy-like behavior. This performance was also not associated with motoric differences in either species. These data demonstrate the utility of touchscreen-delivered progressive ratio tasks in detecting clinically relevant motivational deficits in Huntington's disease. This approach may offer a platform from which clinically relevant mechanistic insights concerning motivation symptoms can be derived and provide an effective route for translation of promising preclinical findings into viable therapeutic interventions.

Effects of nicotine exposure and anxiety on motivation for reward and gambling-like cues under reward uncertainty.

Reward uncertainty is a common characteristic of gambling and may powerfully enhance attraction to gambling-related cues, thus promoting maladaptive gambling behaviors in susceptible individuals. The co-occurrence of gambling disorder with tobacco use disorder (60.4%) suggests a common mechanism for their pathology, and comorbid anxiety (41.3%) might further promote the maintenance of these behaviors. However, it is unknown how nicotine or anxiety might contribute to cue and reward attraction, or promote disordered gambling behavior. In the present study, we investigated the effects of nicotine (0.4 mg/kg, SC) on the desire for uncertain rewards and their cues in male and female Sprague-Dawley rats. During an autoshaping task, rats learned to associate a lever + tone cue with the delivery of sucrose pellet rewards under either certain or uncertain (probability and magnitude) reward conditions. Subsequently, we tested the ability of gambling-like cues to serve as a conditioned reinforcer, and to promote motivation for sucrose rewards during a progressive ratio task. Finally, anxiety behavior was measured to examine its interaction with nicotine and uncertainty. Here, we found that nicotine enhanced attraction to the magazine under certain but not uncertain reward conditions, and increased cue-triggered behaviors. Conversely, in the progressive ratio task, exposure to uncertain conditions and nicotine enhanced motivation for reward, compared with certain conditions. These results suggest that nicotine may interact with both certain and uncertain reward conditions to increase cue-triggered behavior and enhance motivation for rewards, providing possible insight into the comorbid relationship between pathological gambling and tobacco use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Distinguishing between predictive and incentive value of uncertain gambling-like cues in a Pavlovian autoshaping task

The flashing lights and celebratory sounds that dominate slot-machine gambling are believed to promote engagement and motivation to keep playing. However, these cues are often presented in the absence of reward, and previous research suggests that this reward uncertainty, which degrades their predictive value, also increases their incentive value. Here, we used autoshaping to tease apart the impact of reward uncertainty on the predictive and incentive value of a conditioned stimulus (CS) using serial cues. Each CS trial began with the presentation of a predictive CS1, followed by a CS2, holding primarily incentive value, because of its proximity to sucrose reward delivery, under Certain (100%-1) or Uncertain (50%-1-2-3) reward conditions. Subsequently, we tested the impact of amphetamine and nicotine on cue attraction, and the ability of these cues to either serve as a conditioned reinforcer, or promote motivation for sucrose during a progressive ratio task. Finally, we measured anxiety behavior, and examined its interaction with each cue and uncertainty. Our results suggest that reward uncertainty increases attraction to the incentive CS2 and its ability to trigger motivation and reward-seeking. However, although the CS2 is largely ignored under Certain conditions, both CS1 and CS2 become conditioned reinforcers for both groups. Finally, amphetamine reduced the attraction of the CS1 for both groups but had no effect on the attraction of the CS2. These results suggest that reward uncertainty recruits and increases the incentive value of cues with limited predictive value and highlights the distinction between cue attraction, reward-seeking and conditioned reinforcer properties.

AppNL-G-F/NL-G-F mice overall do not show impaired motivation, but cored amyloid plaques in the striatum are inversely correlated with motivation

Apathy is clinically defined as lack of motivation. Apathy is a frequent symptom in patients with Alzheimer's disease (AD). It is unclear whether amyloid β (Aβ) pathology is associated with apathy. To address this question, we employed the AppNL-G-F/NL-G-F mouse, an Aβ deposition-bearing mouse without neurofibrillary tangles and neuronal cell death throughout the lifespan and used a progressive-ratio (PR) task to monitor instrumental motivation between the ages of 16 and 39 weeks. In the PR task, the number of lever presses to receive one reward increases and the number of active lever presses in the final trial a mouse completes represents a break point, which is an index of motivation. During the observation period, AppNL-G-F/NL-G-F mice overall did not show impaired motivation. However, AppNL-G-F/NL-G-F mice showed a dispersion of the break point at 39 weeks of age within the group. Therefore, we examined the association between the degree of the break point and Aβ pathology; the number of cored amyloid plaques in the striatum was inversely correlated with the degree of motivation. Furthermore, we measured the dopamine transporter (DAT) levels in the subcortical tissues including the striatum using western blot analysis and showed that AppNL-G-F/NL-G-F mice have lower DAT levels than do C57BL/6J mice. Although we could not directly determine the effect of core amyloid plaques on the DAT, the results of this study suggest a pathway through which cored amyloid plaques damage the DAT and cause impaired motivation. These results will draw attention to cored amyloid plaques and will aid researchers searching for new strategies that are effective for the prevention and treatment of impaired motivation.

GLP‐1R Role in Cognition and Mood

Major Depressive Disorder (MDD) is a common mental illness that often produces cognitive impairments in patients, hindering affected individuals from performing daily life activities. In 2016, 16.2 million adults had at least one episode of major depression and at least half of these patients also experienced cognitive impairments (National Survey on Drug Use and Health). Current pharmacotherapies for MDD are somewhat effective at treating the symptoms related to affect but are not effective in treating the cognitive impairments associated with MDD. A propitious answer to an effective antidepressant pharmacotherapy for both of these symptoms is being sought in glucagon-like peptide-1 receptor (GLP1-R) agonists. Activation of this receptor plays a role in some types of learning and memory and increases hippocampal neurogenesis, a critical component of antidepressant efficacy. We utilized location discrimination and progressive ratio tasks in laboratory mice to investigate spatial learning and memory and motivation, respectively, hypothesizing that GLP-1R activation would enhance execution of these tasks. Our results demonstrate that GLP-1R activation enhances cognitive performance in the location discrimination task in a sex-dependent manner and negatively affects the motivation measured in the progressive ratio task. These data indicate that GLP-1R has potential to treat cognitive impairments associated with MDD, but its role in improving motivational and mood aspects of MDD requires further investigation. Support or Funding Information Funding provided by R03 MH110749 (DLG), R21DA035588 (GDS), and FSU CRC Planning Grant (DLG), and the FSU College of Medicine. Systemic Ex-4 treatment enhances performance in the LD probe trials (A). Ex-4-treated males performed better in the easy probe trial (B), while Ex-4-treated females performed better in the difficult probe trial (C). *p<0.05 vs. respective SAL, N=11–12/group In females, direct administration of Ex-4 into the brain (icv) did not alter performance in the easy probe LD trial (A), but did improve performance in the more difficult probe test (B). *p<0.001, N=4/group In both sexes, administration of Ex-4 systemically (ip) tended to decrease the number of trials performed in the PR test, suggesting reduced motivation, but statistical significance was not observed. N=8/group. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Increased Hunger, Food Cravings, Food Reward, and Portion Size Selection after Sleep Curtailment in Women Without Obesity.

This study examined the effects of one night of sleep curtailment on hunger, food cravings, food reward, and portion size selection. Women who reported habitually sleeping 7–9 h per night, were aged 18–55, were not obese, and had no sleep disorders were recruited. Sleep conditions in this randomized crossover study consisted of a normal night (NN) and a curtailed night (CN) where time in bed was reduced by 33%. Hunger, tiredness, sleep quality, sleepiness, and food cravings were measured. A progressive ratio task using chocolates assessed the food reward. Participants selected portions of various foods that reflected how much they wanted to eat at that time. The sleep duration was measured using a single-channel electroencephalograph. Twenty-four participants completed the study. The total sleep time was shorter during the CN (p < 0.001). Participants reported increased hunger (p = 0.013), tiredness (p < 0.001), sleepiness (p < 0.001), and food cravings (p = 0.002) after the CN. More chocolate was consumed after the CN (p = 0.004). Larger portion sizes selected after the CN resulted in increased energy plated for lunch (p = 0.034). In conclusion, the present study observed increased hunger, food cravings, food reward, and portion sizes of food after a night of modest sleep curtailment. These maladaptive responses could lead to higher energy intake and, ultimately, weight gain.

Attenuation of satiety gut hormones increases appetitive behavior after curative esophagectomy for esophageal cancer

Reduced appetite and weight loss are common after esophagectomy (ES), and this cohort demonstrates an exaggerated postprandial satiety gut hormone response. Satiety gut hormones modulate food reward, resulting in reduced energy intake. This study aimed to determine the effect of satiety gut hormone modulation by measuring the effect of the somatostatin analog octreotide on appetitive behavior among patients after ES. In this randomized, double-blind, placebo-controlled crossover study, patients ≥1 y after ES and matched controls received either 1 mL 0.9% saline or 1 mL (100 μg) octreotide subcutaneously before completing a progressive ratio task. A measure of appetitive behavior, this task requires subjects to undertake progressively increasing amounts of work to obtain a sweet-fat reinforcer; the final completed increment (breakpoint) represents reinforcer reward value. Separate cohorts were studied in the fasted or 1-h postprandial states. Thirty-six subjects (ES, n=18; matched controls, n=18) were studied. The ES subjects were 2.5±0.3 y postoperation and had a weight loss of 14.6%±2.6% and elevated postprandial glucagon-like peptide 1 compared with controls (49.2±13.4 compared with 20.2±2.3 pM; P=0.04). Octreotide did not alter the breakpoint among ES or control subjects when tested in a fasting condition (ES: 980±371 compared with 1700±584 clicks; P=0.16; controls: 1056±274 compared with 1124±273 clicks; P=0.81). When tested 1 h postprandially, octreotide was associated with an increased breakpoint compared with placebo among ES subjects (322±143 compared with 246±149 clicks; P=0.04) but not controls (248±119 compared with 247±120 clicks; P=0.97). Attenuation of the exaggerated postprandial satiety gut hormone response is associated with increased appetitive behavior toward a sweet-fat stimulus among patients post-ES. Suppression of satiety gut hormones may be a novel target to increase appetite, food intake, and body weight among patients after ES. This study was registered at clinicaltrials.gov as NCT02381249.

Pressing the rewarding button: The relationship between impulsivity, fatigue, and reward sensitivity

This manuscript consists of a study and a direct replication of it examining the interactive effect of self-regulatory depletion and impulsivity on points earned in a progressive ratio task.In study 1 (n = 238), participants first completed a measure of delay discounting. Next, they underwent depletion exercises or control exercises.Finally, they completed a progressive ratio task in which they were able to earn points. Non-depleted people performed the same on this task regardless of their level of impulsivity.However, for depleted people, impulsive people earned the most points. This study suggested that when depleted, people prone to instant gratification will work harder than their less impulsive counterparts to earn rewards. To examine the reliability of these findings, we then did a high-powered, direct replication of this study (n = 782). In the replication, we found null results. This pre-registered, well-powered study suggests the findings of study one were a type I error. The findings of study 2 suggest no effect of self-regulatory attention on tasks related to earning points.

Vertical sleeve gastrectomy in adolescents reduces the appetitive reward value of a sweet and fatty reinforcer in a progressive ratio task

BackgroundAdolescent obesity is challenging to treat even if good multidisciplinary approaches are started early. Vertical sleeve gastrectomy (VSG) is an effective intervention for long-term weight loss, but the underlying mechanisms that result in reduced calorie intake are controversial. Anecdotal evidence from the clinic and evidence in rodents after VSG suggest a decrease in the reward value of high-calorie dense foods. ObjectivesTo determine changes in appetitive behavior of candies (high in sugar and fat) after VSG in adolescents with obesity. SettingUniversity hospital. MethodsSixteen adolescents with obesity (age 15.3 ± .5 yr) who had VSG and 10 control patients (age 13.8 ± .6 yr) who had not undergone surgery were studied. Both groups completed a progressive ratio task by clicking a computer mouse on a progressive ratio schedule to receive a candy high in sugar and fat. In the task, patients were required to expend an increasing amount of effort to obtain the reinforcer until they reach a breakpoint (measure of the reward value of the reinforcer). The task was performed before VSG and 12 and 52 weeks after VSG. ResultsThe VSG group's bodyweight decreased from the baseline 136.6 ± 5.1 to 110.9 ± 5.2 to 87.4 ± 3.7 kg after 12 and 52 weeks, respectively (P < .001). The median breakpoint for candies decreased after VSG from the baseline 320 (160–640) to 80 (50–320) to 160 (80–560) after 12 and 52 weeks, respectively (P = .01). Breakpoints for the control patients did not change (480 [160–640] versus 640 [280–640], P = .17). ConclusionVSG resulted in a reduction in the reward value of a candy, as suggested by the reduced amount of effort adolescents were prepared to expend to obtain the high-sugar and high-fat candy. The effect was most pronounced 12 weeks after surgery but was largely maintained at 1 year. Long-term attenuation of appetitive behavior may be the key to weight loss and weight loss maintenance after VSG in adolescents.

Oxygen responses within the nucleus accumbens are associated with individual differences in effort exertion in rats.

Goal‐directed motivated behaviour is crucial for everyday life. Such behaviour is often measured, in rodents, under a progressive ratio (PR) schedule of reinforcement. Previous studies have identified a few brain structures critical for supporting PR performance. However, the association between neural activity within these regions and individual differences in effort‐related behaviour is not known. Presently, we used constant potential in vivo oxygen amperometry, a surrogate for functional resonance imaging in rodents, to assess changes in tissue oxygen levels within the nucleus accumbens (NAc) and orbitofrontal cortex (OFC) in male Wistar rats performing a PR task. Within both regions, oxygen responses to rewards increased as the effort exerted to obtain the rewards was larger. Furthermore, higher individual breakpoints were associated with greater magnitude NAc oxygen responses. This association could not be explained by temporal confounds and remained significant when controlling for the different number of completed trials. Animals with higher breakpoints also showed greater magnitude NAc oxygen responses to rewards delivered independently of any behaviour. In contrast, OFC oxygen responses were not associated with individual differences in behavioural performance. The present results suggest that greater NAc oxygen responses following rewards, through a process of incentive motivation, may allow organisms to remain on task for longer and to overcome greater effort costs.

PS02.220: ATTENUATION OF SATIETY GUT HORMONES INCREASES APPETITE AFTER CURATIVE ESOPHAGECTOMY FOR ESOPHAGEAL CANCER

Abstract Background Reduced appetite and weight loss after esophagectomy (ES) occur in the context of an exaggerated postprandial satiety gut hormone response. Satiety gut hormones modulate central processing of food reward, resulting in reduced energy intake. The aim of this study was to investigate the effect of satiety gut hormone attenuation using the somatostatin analogue octreotide on appetitive behavior among patients after curative ES. Methods In this randomized, double-blind, placebo-controlled crossover study, disease-free patients at least one year after ES with gastric conduit reconstruction and matched controls received either 1mL 0.9% saline or 1mL (100μg) octreotide subcutaneously, before completing a progressive ratio task (PRT). A measure of appetitive behavior, the PRT requires subjects to undertake progressively increasing amounts of work to obtain a reinforcer—the final completed increment (breakpoint) representing reinforcer reward value in different states. Separate cohorts were studied in the fasted or 1-hour postprandial states. The institutional Research Ethics Committee approved the study (REC 2015/21/02), which was registered on ClinicalTrials.gov prior to recruitment of the first participant (NCT02381249). Results 36 subjects (ES, n = 18, matched controls, n = 18) were studied. 2.5 ± 0.3 years postoperatively, ES patients demonstrated 14.6 ± 2.6% weight loss and an elevated postprandial GLP-1 (49.2 ± 13.4 versus controls with 20.2 ± 2.3 pM, P = 0.038). Octreotide did not alter appetite among ES or control subjects when tested fasting (breakpoint, ES: 980 ± 371 versus 1700 ± 583, P = 0.16; control: 1056 ± 274 versus 1124 ± 273, P = 0.80). When tested one hour postprandially, octreotide was associated with increased appetitive behavior versus placebo among ES subjects (breakpoint, 322 ± 143 versus 246 ± 149, P = 0.037), but not controls (248 ± 119 versus 247 ± 120, P = 0.98). Conclusion Attenuation of the exaggerated postprandial satiety gut hormone response is associated with increased appetitive behavior towards a sweet-fat stimulus among patients post ES. Suppression of satiety gut hormones may represent a novel target to increase appetite, food intake and body weight in patients after esophagectomy. Disclosure All authors have declared no conflicts of interest.

Modulation of appetitive motivation by prefrontal cortical mu-opioid receptors is dependent upon local dopamine D1 receptor signaling

Opioid neurotransmission has been implicated in psychiatric disorders featuring impaired control over appetitive motivation, such as addiction and binge-eating disorder. We have previously shown that infusions of the μ-opioid receptor (μOR) agonist DAMGO into the ventromedial prefrontal cortex (vmPFC) induced hyperphagia, increased motor activity, and augmented sucrose-reinforced responding in the task progressive ratio (PR) task, which assesses the motivational value of an incentive. These effects were not reproduced by intra-PFC infusion of a variety of dopamine (DA) agonists and antagonists, suggesting that manipulation of intra-PFC DA systems alone is not sufficient to reproduce μOR-like effects. Nevertheless, this does not rule out interactions between PFC DA and μ-opioid systems. Here we used intra-vmPFC drug cocktails containing DAMGO and SCH 23390 (a DA D1 receptor antagonist) to determine whether increases in appetitive motivation and motor activity elicited by intra-vmPFC μOR stimulation require intact signaling through vmPFC D1 receptors. Blockade of D1 receptors with SCH 23390 attenuated the enhancement of PR breakpoint, and increases in exploratory-like behavior and feeding initiation elicited by intra-vmPFC μOR stimulation. These results establish that intra-vmPFC D1 signaling is required for the expression of behavioral effects evoked by μOR stimulation within the PFC, and further suggest that D1 tone plays an enabling or permissive role in the expression of μOR –elicited effects. Simultaneous targeting of both μ-opioid and D1 systems may represent a more efficacious treatment strategy (compared to μOR blockade alone) for psychiatric disorders characterized by dysregulated appetitive motivation.

Validation and optimisation of a touchscreen progressive ratio test of motivation in male rats

RationaleAcross species, effort-related motivation can be assessed by testing behaviour under a progressive ratio (PR) schedule of reinforcement. However, to date, PR tasks for rodents have been available using traditional operant response systems only.ObjectivesTouchscreen operant response systems allow the assessment of behaviour in laboratory rodents, using tasks that share high face validity with the computerised assessments used in humans. Here, we sought to optimise a rat touchscreen variant of PR and validate it by assessing the effects of a number of manipulations known to affect PR performance in non-touchscreen paradigms.MethodsSeparate groups of male Sprague-Dawley rats were trained on PR schedules with either linear (PR4) or exponential (PREXP) schedules of reinforcement. PR performance was assessed in response to manipulations in reward outcome. Animals were tested under conditions of increased reward magnitude and following reward devaluation through a prefeeding procedure. Subsequently, the effects of systemic administration of the dopamine D2/D3 receptor antagonist raclopride and the psychostimulant d-amphetamine were examined as traditional pharmacological methods for manipulating motivation.ResultsRats reinforced under PR4 and PREXP schedules consistently showed differential patterns of response rates within sessions. Furthermore, both PR4 and PREXP schedules were sensitive to suppression by prefeeding or raclopride administration. Performance under both schedules was facilitated by increasing reward magnitude or d-amphetamine administration.ConclusionsTaken together, these findings mirror those observed in lever-based PR paradigms in rats. This study therefore demonstrates the successful validation of the rat touchscreen PR task. This will allow for the assessment of motivation in rats, within the same touchscreen apparatus used for the assessment of complex cognitive processes in this species.

Motivational changes that develop in a mouse model of inflammation-induced depression are independent of indoleamine 2,3 dioxygenase.

Despite years of research, our understanding of the mechanisms by which inflammation induces depression is still limited. As clinical data points to a strong association between depression and motivational alterations, we sought to (1) characterize the motivational changes that are associated with inflammation in mice, and (2) determine if they depend on inflammation-induced activation of indoleamine 2,3 dioxygenase-1 (IDO1). Lipopolysaccharide (LPS)-treated or spared nerve injured (SNI) wild type (WT) and Ido1-/- mice underwent behavioral tests of antidepressant activity (e.g., forced swim test) and motivated behavior, including assessment of (1) reward expectancy using a food-related anticipatory activity task, (2) willingness to work for reward using a progressive ratio schedule of food reinforcement, (3) effort allocation using a concurrent choice task, and (4) ability to associate environmental cues with reward using conditioned place preference. LPS- and SNI-induced deficits in behavioral tests of antidepressant activity in WT but not Ido1-/- mice. Further, LPS decreased food related-anticipatory activity, reduced performance in the progressive ratio task, and shifted effort toward the preferred reward in the concurrent choice task. These effects were observed in both WT and Ido1-/- mice. Finally, SNI mice developed a conditioned place preference based on relief from pain in an IDO1-independent manner. These findings demonstrate that the motivational effects of inflammation do not require IDO1. Further, they indicate that the motivational component of inflammation-induced depression is mechanistically distinct from that measured by behavioral tests of antidepressant activity.

Nucleus Accumbens Microcircuit Underlying D2-MSN-Driven Increase in Motivation.

The nucleus accumbens (NAc) plays a central role in reinforcement and motivation. Around 95% of the NAc neurons are medium spiny neurons (MSNs), divided into those expressing dopamine receptor D1 (D1R) or dopamine receptor D2 (D2R). Optogenetic activation of D2-MSNs increased motivation, whereas inhibition of these neurons produced the opposite effect. Yet, it is still unclear how activation of D2-MSNs affects other local neurons/interneurons or input terminals and how this contributes for motivation enhancement. To answer this question, in this work we combined optogenetic modulation of D2-MSNs with in loco pharmacological delivery of specific neurotransmitter antagonists in rats. First, we showed that optogenetic activation of D2-MSNs increases motivation in a progressive ratio (PR) task. We demonstrated that this behavioral effect relies on cholinergic-dependent modulation of dopaminergic signalling of ventral tegmental area (VTA) terminals, which requires D1R and D2R signalling in the NAc. D2-MSN optogenetic activation decreased ventral pallidum (VP) activity, reducing the inhibitory tone to VTA, leading to increased dopaminergic activity. Importantly, optogenetic activation of D2-MSN terminals in the VP was sufficient to recapitulate the motivation enhancement. In summary, our data suggests that optogenetic stimulation of NAc D2-MSNs indirectly modulates VTA dopaminergic activity, contributing for increased motivation. Moreover, both types of dopamine receptors signalling in the NAc are required in order to produce the positive behavioral effects.

Early Detection of Apathetic Phenotypes in Huntington\u2019s Disease Knock-in Mice Using Open Source Tools

Apathy is one of the most prevalent and progressive psychiatric symptoms in Huntington’s disease (HD) patients. However, preclinical work in HD mouse models tends to focus on molecular and motor, rather than affective, phenotypes. Measuring behavior in mice often produces noisy data and requires large cohorts to detect phenotypic rescue with appropriate power. The operant equipment necessary for measuring affective phenotypes is typically expensive, proprietary to commercial entities, and bulky which can render adequately sized mouse cohorts as cost-prohibitive. Thus, we describe here a home-built, open-source alternative to commercial hardware that is reliable, scalable, and reproducible. Using off-the-shelf hardware, we adapted and built several of the rodent operant buckets (ROBucket) to test HttQ111/+ mice for attention deficits in fixed ratio (FR) and progressive ratio (PR) tasks. We find that, despite normal performance in reward attainment in the FR task, HttQ111/+ mice exhibit reduced PR performance at 9–11 months of age, suggesting motivational deficits. We replicated this in two independent cohorts, demonstrating the reliability and utility of both the apathetic phenotype, and these ROBuckets, for preclinical HD studies.

Housing and testing in mixed-sex rooms increases motivation and accuracy during operant testing in both male and female mice.

Operant behavior tasks are widely used in neuroscience research, but little is known about how variables such as housing and testing conditions affect rodent operant performance. We have previously observed differences in operant performance in male and female mice depending on whether mice were housed and tested in rooms containing only one sex versus rooms containing both sexes. Here, male and female mice in either single-sex or mixed sex housing rooms were trained on fixed ratio 1 (FR1) and progressive ratio (PR) tasks. For both sexes, animals in the mixed sex room had more accurate performance in FR1 and were more motivated in the PR task. We then moved the single sex housed animals to the mixed sex room and vice versa. Animals that started in mixed sex housing had no change to PR, but both sexes who started in single sex housing were more motivated after the switch. Additionally, the females that moved into single-sex housing performed less accurately in FR1. We conclude that housing and testing conditions can affect performance on FR1 and PR tasks. As these tasks are commonly used as training steps to more complex tasks, housing and testing conditions should be carefully considered during experiment design and reported in publications.

Phencyclidine increased while isolation rearing did not affect progressive ratio responding in rats: Investigating potential models of amotivation in schizophrenia

BackgroundSchizophrenia is a debilitating neurodevelopmental disorder affecting 1% of the global population with heterogeneous symptoms including positive, negative, and cognitive. While treatment for positive symptoms exists, none have been developed to treat negative symptoms. Animal models of schizophrenia are required to test targeted treatments and since patients exhibit reduced effort (breakpoints) for reward in a progressive ratio (PR) task, we examined the PR breakpoints of rats treated with the NMDA receptor antagonist phencyclidine or those reared in isolation – two common manipulations used to induce schizophrenia-relevant behaviors in rodents. MethodsIn two cohorts, the PR breakpoint for a palatable food reward was examined in Long Evans rats after: 1) a repeated phencyclidine regimen; 2) A subchronic phencyclidine regimen followed by drug washout; and 3) post-weaning social isolation. ResultsRats treated with repeated phencyclidine and those following washout from phencyclidine exhibited higher PR breakpoints than vehicle-treated rats. The breakpoint of isolation reared rats did not differ from those socially reared, despite abnormalities of these rats in other schizophrenia-relevant behaviors. ConclusionDespite their common use for modeling other schizophrenia-relevant behaviors neither phencyclidine treatment nor isolation rearing recreated the motivational deficits observed in patients with schizophrenia, as measured by PR breakpoint. Other manipulations, and negative symptom-relevant behaviors, require investigation prior to testing putative therapeutics.