Measuring Motivation and Reward-Related Decision Making in the Rodent Operant Touchscreen System.

This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/0471142301.ns0834s74This unit is designed to facilitate implementation of the fixed and progressive ratio paradigms and the effort-related choice task in the rodent touchscreen apparatus to permit direct measurement of motivation and reward-related decision making in this equipment. These protocols have been optimized for use in the mouse and reliably yield stable performance levels that can be enhanced or suppressed by systemic pharmacological manipulation. Instructions are also provided for the adjustment of task parameters to permit use in mouse models of neurodegenerative disease. These tasks expand the utility of the rodent touchscreen apparatus beyond the currently available battery of cognitive assessment paradigms.The protocols presented in this Unit were developed and optimized as part of a research program funded by Wellcome Trust grant 089703/Z/09/Z awarded to TJB and LMS. TJB and LMS also received funding from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007- 2013). TJB and LMS consult for Campden Instruments Ltd

Selective effects of 5-HT2C receptor modulation on performance of a novel valence-probe visual discrimination task and probabilistic reversal learning in mice.

RATIONALE: Dysregulation of the serotonin (5-HT) system is a pathophysiological component in major depressive disorder (MDD), a condition closely associated with abnormal emotional responsivity to positive and negative feedback. However, the precise mechanism through which 5-HT tone biases feedback responsivity remains unclear. 5-HT2C receptors (5-HT2CRs) are closely linked with aspects of depressive symptomatology, including abnormalities in reinforcement processes and response to stress. Thus, we aimed to determine the impact of 5-HT2CR function on response to feedback in biased reinforcement learning. METHODS: We used two touchscreen assays designed to assess the impact of positive and negative feedback on probabilistic reinforcement in mice, including a novel valence-probe visual discrimination (VPVD) and a probabilistic reversal learning procedure (PRL). Systemic administration of a 5-HT2CR agonist and antagonist resulted in selective changes in the balance of feedback sensitivity bias on these tasks. RESULTS: Specifically, on VPVD, SB 242084, the 5-HT2CR antagonist, impaired acquisition of a discrimination dependent on appropriate integration of positive and negative feedback. On PRL, SB 242084 at 1 mg/kg resulted in changes in behaviour consistent with reduced sensitivity to positive feedback. In contrast, WAY 163909, the 5-HT2CR agonist, resulted in changes associated with increased sensitivity to positive feedback and decreased sensitivity to negative feedback. CONCLUSIONS: These results suggest that 5-HT2CRs tightly regulate feedback sensitivity bias in mice with consequent effects on learning and cognitive flexibility and specify a framework for the influence of 5-HT2CRs on sensitivity to reinforcement

Accumbal Cholinergic Interneurons Differentially Influence Motivation Related to Satiety Signaling

Satiety, rather than all or none, can instead be viewed as a cumulative decrease in the drive to eat that develops over the course of a meal. The nucleus accumbens (NAc) is known to play a critical role in this type of value reappraisal, but the underlying circuits that influence such processes are unclear. Although NAc cholinergic interneurons (CINs) comprise only a small proportion of NAc neurons, their local impact on reward-based processes provides a candidate cell population for investigating the neural underpinnings of satiety. The present research therefore aimed to determine the role of NAc-CINs in motivation for food reinforcers in relation to satiety signaling. Through bidirectional control of CIN activity in mice, we show that when motivated by food restriction, increasing CIN activity led to a reduction in palatable food consumption while reducing CIN excitability enhanced food intake. These activity-dependent changes developed only late in the session and were unlikely to be driven by the innate reinforcer strength, suggesting that CIN modulation was instead impacting the cumulative change in motivation underlying satiety signaling. We propose that on a circuit level, an overall increase in inhibitory tone onto NAc output neurons played a role in the behavioral results, as activating NAc-CINs led to an inhibition of medium spiny neurons that was dependent on nicotinic receptor activation. Our results reveal an important role for NAc-CINs in controlling motivation for food intake and additionally provide a circuit-level framework for investigating the endogenous cholinergic circuits that signal satiety.Peer reviewe

Coexistence of perseveration and apathy in the TDP-43Q331K knock-in mouse model of ALS-FTD.

Funder: Motor Neurone Disease Association (MNDA); doi: https://doi.org/10.13039/501100000406Funder: the Lady Edith Wolfson Fellowship Fund, the van Geest FoundationPerseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS-FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS-FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS-FTD

Assessment of mGluR5 KO mice under conditions of low stress using a rodent touchscreen apparatus reveals impaired behavioural flexibility driven by perseverative responses

Genetic and pharmacological manipulations targeting metabotropic glutamate receptor 5 (mGluR5) affect performance in behavioural paradigms that depend on cognitive flexibility. Many of these studies involved exposing mice to highly stressful conditions including electric foot shocks or water immersion and forced swimming. Because mGluR5 is also implicated in resilience and stress responses, however, apparent impairments in inhibitory learning may have been an artifact of manipulation-induced changes in affective state. To address this, we present here a characterization of cognitive flexibility in mGluR5 knockout (KO) mice conducted with a rodent touchscreen cognitive assessment apparatus in which the animals experience significantly less stress. Our results indicate a significant reversal learning impairment relative to wild-type (WT) controls in the two-choice Visual Discrimination-Reversal (VDR) paradigm. Upon further analysis, we found that this deficit is primarily driven by a prolonged period of perseveration in the early phase of reversal. We also observed a similar perseveration phenotype in the KO mice in the Extinction (EXT) paradigm. In addition, mGluR5 KO mice show higher breakpoints in the touchscreen Progressive Ratio (PR) and altered decision making in the Effort-related Choice (ERC) tasks. Interestingly, this impairment in PR is an additional manifestation of an increased propensity to perseverate on the emission of relatively simplistic behavioural outputs. Together, these findings suggest that under conditions of low stress, mGluR5 KO mice exhibit a pronounced perseverative phenotype that blunts cognitive flexibility

Coexistence of perseveration and apathy in the TDP-43\u3csup\u3eQ331K\u3c/sup\u3e knock-in mouse model of ALS–FTD

© 2020, The Author(s). Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS–FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS–FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS–FTD

Coexistence of perseveration and apathy in the TDP-43^Q331K knock-in mouse model of ALS–FTD

Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS–FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS–FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS–FTD

Refining the study of decision-making in animals: differential effects of d-amphetamine and haloperidol in a novel touchscreen-automated Rearing-Effort Discounting (RED) task and the Fixed-Ratio Effort Discounting (FRED) task

Effort-based decision-making is impaired in multiple psychopathologies leading to significant impacts on the daily life of patients. Preclinical studies of this important transdiagnostic symptom in rodents are hampered, however, by limitations present in currently available decision-making tests, including the presence of delayed reinforcement and off-target cognitive demands. Such possible confounding factors can complicate the interpretation of results in terms of decision-making per se. In this study we addressed this problem using a novel touchscreen Rearing-Effort Discounting (RED) task in which mice choose between two single-touch responses: rearing up to touch an increasingly higher positioned stimulus to obtain a High Reward (HR) or touching a lower stimulus to obtain a Low Reward (LR). To explore the putative advantages of this new approach, RED was compared with a touchscreen version of the well-studied Fixed Ratio-based Effort Discounting (FRED) task, in which multiple touches are required to obtain an HR, and a single response is required to obtain an LR. Results from dopaminergic (haloperidol and d-amphetamine), behavioral (changes in the order of effort demand; fixed-ratio schedule in FRED or response height in RED), and dietary manipulations (reward devaluation by pre-feeding) were consistent with the presence of variables that may complicate interpretation of conventional decision-making tasks, and demonstrate how RED appears to minimize such variables

Optimizing reproducibility of operant testing through reinforcer standardization: identification of key nutritional constituents determining reward strength in touchscreens.

Reliable and reproducible assessment of animal learning and behavior is a central aim of basic and translational neuroscience research. Recent developments in automated operant chamber technology have led to the possibility of universal standard protocols, in addition to increased translational potential, reliability and accuracy. However, the impact of regional and national differences in the supplies of available reinforcers in this system on behavioural performance and inter-laboratory variability is an unknown and at present uncontrolled variable. Therefore, we aimed to identify which constituent(s) of the reward determines reinforcer strength to enable improved standardization of this parameter across laboratories. Male C57BL/6 mice were examined in the touchscreen-based fixed ratio (FR) and progressive ratio (PR) schedules, reinforced with different kinds of milk-based reinforcers to directly compare the incentive values of plain milk (PM, high-calorie: high-fat/low-sugar), strawberry-flavored milk (SM, high-calorie: low-fat/high-sugar), and semi-skimmed low-fat milk (LM, low-calorie: low-fat/low-sugar) on the basis of differences in caloric content, sugar/fat content, and flavor. Use of a higher caloric content reward was effective in increasing operant training acquisition rate. Total trial number completed in FR and breakpoint in PR were higher using the two isocaloric milk products (PM and SM) than the lower caloric LM, with comparable outcomes between PM and SM conditions, suggesting that total caloric content determines reward strength. Analysis of within-session changes in response rate revealed that overall outputs in FR and PR primarily depend on the response rate at the initial phase of a session, which itself was dependent on reinforcer caloric content. Interestingly, the rate of satiation, indicated by decay in response rate within a FR session, was highest when reinforced with SM, suggesting a rapid satiating effect of sugar. The key contribution of reward caloric content to operant performance was confirmed in a multi-laboratory study using the touchscreen 5-choice serial reaction time task (5-CSRTT) reinforced by two isocaloric milk-based liquid rewards with different countries of origin, which yielded consistent performance parameters across sites. Our results indicate that milk-based liquid reinforcer standardization can be facilitated by matching caloric content across laboratories despite regional or national differences in other non-caloric aspects of the reinforcers

Dopamine D2-like receptor stimulation blocks negative feedback in visual and spatial reversal learning in the rat: behavioural and computational evidence

Abstract: Rationale: Dopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson’s disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear. Objectives: We tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback. Methods: Male Lister Hooded rats were trained on a novel visual reversal learning task. Performance on “probe trials”, during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback. The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism. Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors. Results: D2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials. Conclusions: D2R stimulation impairs reversal learning by blocking the impact of negative feedback