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Lopez-Cruz L, Phillips BU, Hailwood JM, Saksida LM, Heath CJ, Bussey TJ. 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. Neuropsychopharmacology 2024; 49:422-432. [PMID: 37644210 PMCID: PMC10724152 DOI: 10.1038/s41386-023-01707-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 07/14/2023] [Accepted: 07/31/2023] [Indexed: 08/31/2023]
Abstract
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.
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Affiliation(s)
- Laura Lopez-Cruz
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
- School of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
| | - Benjamin U Phillips
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK
| | - Jonathan M Hailwood
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK
| | - Lisa M Saksida
- Robarts Research Institute and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada
| | - Christopher J Heath
- School of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
| | - Timothy J Bussey
- Robarts Research Institute and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada
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2
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Canonica T, Zalachoras I. Motivational disturbances in rodent models of neuropsychiatric disorders. Front Behav Neurosci 2022; 16:940672. [PMID: 36051635 PMCID: PMC9426724 DOI: 10.3389/fnbeh.2022.940672] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Motivated behavior is integral to the survival of individuals, continuously directing actions toward rewards or away from punishments. The orchestration of motivated behavior depends on interactions among different brain circuits, primarily within the dopaminergic system, that subserve the analysis of factors such as the effort necessary for obtaining the reward and the desirability of the reward. Impairments in motivated behavior accompany a wide range of neuropsychiatric disorders, decreasing the patients’ quality of life. Despite its importance, motivation is often overlooked as a parameter in neuropsychiatric disorders. Here, we review motivational impairments in rodent models of schizophrenia, depression, and Parkinson’s disease, focusing on studies investigating effort-related behavior in operant conditioning tasks and on pharmacological interventions targeting the dopaminergic system. Similar motivational disturbances accompany these conditions, suggesting that treatments aimed at ameliorating motivation levels may be beneficial for various neuropsychiatric disorders.
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3
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Deane AR, Ward RD. The instrumental role of operant paradigms in translational psychiatric research: Insights from a maternal immune activation model of schizophrenia risk. J Exp Anal Behav 2022; 117:560-575. [PMID: 35319781 PMCID: PMC9314699 DOI: 10.1002/jeab.753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/01/2022] [Accepted: 02/18/2022] [Indexed: 11/18/2022]
Abstract
Rigorous behavioral analysis is essential to the translation of research conducted using animal models of neuropsychiatric disease. Here we discuss the use of operant paradigms within our lab as a powerful approach for exploring the biobehavioral bases of disease in the maternal immune activation rat model of schizophrenia. We have investigated a range of disease features in schizophrenia including abnormal perception of time, cognition, learning, motivation, and internal state (psychosis), providing complex insights into brain and behavior. Beyond simple phenotyping, implementing sophisticated operant procedures has been effective in delineating aspects of pathological behavior, identifying interacting pathologies, and isolating contributing mechanisms of disease. We provide comment on the strengths of operant techniques to support high-quality behavioral investigations in fundamental neuropsychiatric research.
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Affiliation(s)
- Ashley R. Deane
- New Zealand Brain Research InstituteChristchurchNew Zealand
- Department of MedicineUniversity of OtagoChristchurchNew Zealand
| | - Ryan D. Ward
- Department of PsychologyUniversity of OtagoDunedinNew Zealand
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4
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Hu Y, van Wingerden M, Sellitto M, Schäble S, Kalenscher T. Anterior Cingulate Cortex Lesions Abolish Budget Effects on Effort-Based Decision-Making in Rat Consumers. J Neurosci 2021; 41:4448-4460. [PMID: 33753545 PMCID: PMC8152606 DOI: 10.1523/jneurosci.2541-20.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 02/26/2021] [Accepted: 02/27/2021] [Indexed: 11/21/2022] Open
Abstract
Demand theory can be applied to analyze how animal consumers change their selection of commodities in response to changes in commodity prices, given budget constraints. Previous work has shown that demand elasticities in rats differed between uncompensated budget conditions in which the budget available to be spent on the commodities (e.g., the finite number of discrete operants to "purchase" rewards in two-alternative fixed-ratio schedules) was kept constant, and compensated budget conditions in which the budget was adjusted so that consumers could potentially continue to obtain the original reward bundles. Here, we hypothesized that rat anterior cingulate cortex (ACC) was necessary to produce this budget effect on demand elasticities. We applied excitotoxic or sham lesions to ACC in rats performing an effort task in which the prices of liquid vanilla or chocolate rewards (the effort required to obtain rewards) and the budget (the total number of operants) was manipulated. When reward prices changed, and the budget was compensated, all rats adjusted their demand for chocolate and vanilla accordingly. In sham-lesioned rats, changes in demand were even more pronounced when the budget was not compensated for the price changes. By contrast, ACC-lesioned animals did not show this additional budget effect. An in-depth comparison of the rats' choice patterns showed that, unlike sham rats, ACC-lesioned animals failed to maximize session-bundle utility after price/budget changes, revealing deficits in higher-order choice-strategy adaptations. Our results suggest a novel role of ACC in considering purchasing power during complex cost-benefit value computations.SIGNIFICANCE STATEMENT Anterior cingulate cortex (ACC) is important for allocating effort in cost-benefit calculations in animals and humans. Economic theory prescribes that the value of the costs in cost-benefit analyses not only depends on the net nominal costs required to purchase a reward, but also on the available budget resources, i.e., on the budget's "purchasing value." We asked whether ACC, a region implicated in effort-based decision-making and reward comparisons, is required for computing the value of effort relative to a budget constraint. Applying demand theory to describe rat choices in a rodent effort allocation task with varying effort prices and budgets, we show that ACC integrity was necessary for computing purchasing power, a core variable in economic choice theory.
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Affiliation(s)
- Yue Hu
- Comparative Psychology, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany
| | - Marijn van Wingerden
- Department of Cognitive Science and Artificial Intelligence, Tilburg University, Tilburg 5037 AB, The Netherlands
| | - Manuela Sellitto
- Comparative Psychology, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany
| | - Sandra Schäble
- Comparative Psychology, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany
| | - Tobias Kalenscher
- Comparative Psychology, Institute of Experimental Psychology, Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany
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5
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Timing behavior in genetic murine models of neurological and psychiatric diseases. Exp Brain Res 2021; 239:699-717. [PMID: 33404792 DOI: 10.1007/s00221-020-06021-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 12/16/2020] [Indexed: 01/17/2023]
Abstract
How timing behavior is altered in different neurodevelopmental and neurodegenerative disorders is a contemporary research question. Genetic murine models (GMM) that offer high construct validity also serve as useful tools to investigate this question. But the literature on timing behavior of different GMMs largely remains to be consolidated. The current paper addresses this gap by reviewing studies that have been conducted with GMMs of neurodevelopmental (e.g. ADHD, schizophrenia, autism spectrum disorder), neurodegenerative disorders (e.g., Alzheimer's disease, Huntington's disease) as well as circadian and other mutant lines. The review focuses on those studies that specifically utilized the peak interval procedure to improve the comparability of findings both within and between different disease models. The reviewed studies revealed timing deficits that are characteristic of different disorders. Specifically, Huntington's disease models had weaker temporal control over the termination of their anticipatory responses, Alzheimer's disease models had earlier timed responses, schizophrenia models had weaker temporal control, circadian mutants had shifted timed responses consistent with shifts in the circadian periods. The differences in timing behavior were less consistent for other conditions such as attention deficit and hyperactivity disorder and mutations related to intellectual disability. We discuss the implications of these findings for the neural basis of an internal stopwatch. Finally, we make methodological recommendations for future research for improving the comparability of the timing behavior across different murine models.
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Elcoro M, Backer A. Murray Sidman and Patient H. M.: The role of behavior analysis in the emergence of collaborative modern neuroscience. J Exp Anal Behav 2020; 115:242-254. [PMID: 33319374 DOI: 10.1002/jeab.656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/12/2020] [Accepted: 11/15/2020] [Indexed: 11/09/2022]
Abstract
The intersection of the lives of 2 essential individuals in science, behavior analyst Murray Sidman (1923-2019), and Henry G. Molaison also known as Patient H.M. (1926-2008), warrants examination as it highlights the role of behavior analysis and other disciplines in the emergence of modern neuroscience and a collaborative approach to science. This paper describes the historical context and content of two publications by Sidman in which Molaison served as a research participant. The goal of the present paper is to emphasize this little-known facet of Sidman's rich career and to highlight the pioneering role of behavior analysis, and particularly the work of Murray Sidman, in the emergence of collaborative modern neuroscience.
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Kim E, White MA, Phillips BU, Lopez-Cruz L, Kim H, Heath CJ, Lee JE, Saksida LM, Sreedharan J, Bussey TJ. Coexistence of perseveration and apathy in the TDP-43 Q331K knock-in mouse model of ALS-FTD. Transl Psychiatry 2020; 10:377. [PMID: 33149110 PMCID: PMC7643138 DOI: 10.1038/s41398-020-01078-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 05/21/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
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.
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Affiliation(s)
- Eosu Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
| | - Matthew A White
- Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Benjamin U Phillips
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Laura Lopez-Cruz
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
- School of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, UK
| | - Hyunjeong Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
- Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Christopher J Heath
- School of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, UK
| | - Jong Eun Lee
- Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Lisa M Saksida
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
- Molecular Medicine Research Laboratories, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
- The Brain and Mind Institute, Western University, London, ON, Canada
| | - Jemeen Sreedharan
- Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
| | - Timothy J Bussey
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
- Molecular Medicine Research Laboratories, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
- The Brain and Mind Institute, Western University, London, ON, Canada.
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8
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Balcı F, Freestone D. The Peak Interval Procedure in Rodents: A Tool for Studying the Neurobiological Basis of Interval Timing and Its Alterations in Models of Human Disease. Bio Protoc 2020; 10:e3735. [PMID: 33659396 PMCID: PMC7854006 DOI: 10.21769/bioprotoc.3735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 11/02/2022] Open
Abstract
Animals keep track of time intervals in the seconds to minutes range with, on average, high accuracy but substantial trial-to-trial variability. The ability to detect the statistical signatures of such timing behavior is an indispensable feature of a good and theoretically-tractable testing procedure. A widely used interval timing procedure is the peak interval (PI) procedure, where animals learn to anticipate rewards that become available after a fixed delay. After learning, they cluster their responses around that reward-availability time. The in-depth analysis of such timed anticipatory responses leads to the understanding of an internal timing mechanism, that is, the processing dynamics and systematic biases of the brain's clock. This protocol explains in detail how the PI procedure can be implemented in rodents, from training through testing to analysis. We showcase both trial-by-trial and trial-averaged analytical methods as a window into these internal processes. This protocol has the advantages of capturing timing behavior in its full-complexity in a fashion that allows for a theoretical treatment of the data.
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Affiliation(s)
- Fuat Balcı
- Koç University, Department of Psychology, Istanbul, Turkey
| | - David Freestone
- William Paterson University, Department of Psychology, NJ, United States
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9
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Heath CJ, O'Callaghan C, Mason SL, Phillips BU, Saksida LM, Robbins TW, Barker RA, Bussey TJ, Sahakian BJ. A Touchscreen Motivation Assessment Evaluated in Huntington's Disease Patients and R6/1 Model Mice. Front Neurol 2019; 10:858. [PMID: 31447770 PMCID: PMC6696591 DOI: 10.3389/fneur.2019.00858] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 07/24/2019] [Indexed: 12/18/2022] Open
Abstract
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.
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Affiliation(s)
- Christopher J. Heath
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
- School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom
| | - Claire O'Callaghan
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
- Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
| | - Sarah L. Mason
- John van Geest Centre for Brain Repair, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - Benjamin U. Phillips
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
| | - Lisa M. Saksida
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Trevor W. Robbins
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
| | - Roger A. Barker
- John van Geest Centre for Brain Repair, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - Timothy J. Bussey
- Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Barbara J. Sahakian
- Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
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10
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DeRosse P, Barber AD, Fales CL, Malhotra AK. Deconstructing Avolition: Initiation vs persistence of reward-directed effort. Psychiatry Res 2019; 273:647-652. [PMID: 31207847 PMCID: PMC7864548 DOI: 10.1016/j.psychres.2019.01.073] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 01/23/2019] [Accepted: 01/23/2019] [Indexed: 10/27/2022]
Abstract
Avolition, a decrease in the initiation and persistence of goal-directed behavior, is a critical determinant of disability in patients with schizophrenia. Recent studies have demonstrated that avolition can be modeled using reward-based, behavioral paradigms. These studies suggest that avolition represents a motivational deficit, accounted for by a diminished ability to anticipate pleasurable experiences. Notably, although data suggest that "initiation" and "persistence" of goal-directed behavior may depend on different processes, few studies have sought to distinguish between these two components of avolitional symptoms. Such distinctions could have real consequences for the development and evaluation of interventions designed to ameliorate avolitional symptoms. Thus, the present study examined the relationship between anticipatory pleasure, a key driver of avolition, and both the initiation and persistence of reward-directed, effortful responding during the Effort Expenditures for Rewards Task in 103 healthy participants. We found that anticipatory pleasure was not significantly predictive of the initiation of effortful responding but was significantly predictive of the persistence of effortful responding; most notably when the probabilities of reward and non-reward were equivalent. These data suggest that although deficits in reward processes contribute to the likelihood of persisting in reward-driven behavior, they contribute little to the initiation of such behavior.
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Affiliation(s)
- Pamela DeRosse
- The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, NY, USA.
| | - Anita D Barber
- The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, NY, USA
| | - Christina L Fales
- The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, NY, USA
| | - Anil K Malhotra
- The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA; Division of Psychiatry Research, The Zucker Hillside Hospital, Division of Northwell Health, Glen Oaks, NY, USA
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11
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Translational tests involving non-reward: methodological considerations. Psychopharmacology (Berl) 2019; 236:449-461. [PMID: 30306228 PMCID: PMC6373191 DOI: 10.1007/s00213-018-5062-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 10/02/2018] [Indexed: 02/07/2023]
Abstract
This review is concerned with methods for assessing the processing of unrewarded responses in experimental animals and the mechanisms underlying performance of these tasks. A number of clinical populations, including Parkinson's disease, depression, compulsive disorders, and schizophrenia demonstrate either abnormal processing or learning from non-rewarded responses in laboratory-based reinforcement learning tasks. These effects are hypothesized to result from disturbances in modulatory neurotransmitter systems, including dopamine and serotonin. Parallel work in experimental animals has revealed consistent behavioral patterns associated with non-reward and, consistent with the human literature, modulatory roles for specific neurotransmitters. Classical tests involving an important reward omission component include appetitive extinction, ratio schedules of responding, reversal learning, and delay and probability discounting procedures. In addition, innovative behavioral tests have recently been developed leverage probabilistic feedback to specifically assay accommodation of, and learning from, non-rewarded responses. These procedures will be described and reviewed with discussion of the behavioral and neural determinants of performance. A final section focusses specifically on the benefits of trial-by-trial analysis of responding during such tasks, and the implications of such analyses for the translation of findings to clinical studies.
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12
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Optimisation of cognitive performance in rodent operant (touchscreen) testing: Evaluation and effects of reinforcer strength. Learn Behav 2018; 45:252-262. [PMID: 28205186 PMCID: PMC5565648 DOI: 10.3758/s13420-017-0260-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Operant testing is a widely used and highly effective method of studying cognition in rodents. Performance on such tasks is sensitive to reinforcer strength. It is therefore advantageous to select effective reinforcers to minimize training times and maximize experimental throughput. To quantitatively investigate the control of behavior by different reinforcers, performance of mice was tested with either strawberry milkshake or a known powerful reinforcer, super saccharin (1.5% or 2% (w/v) saccharin/1.5% (w/v) glucose/water mixture). Mice were tested on fixed (FR)- and progressive-ratio (PR) schedules in the touchscreen-operant testing system. Under an FR schedule, both the rate of responding and number of trials completed were higher in animals responding for strawberry milkshake versus super saccharin. Under a PR schedule, mice were willing to emit similar numbers of responses for strawberry milkshake and super saccharin; however, analysis of the rate of responding revealed a significantly higher rate of responding by animals reinforced with milkshake versus super saccharin. To determine the impact of reinforcer strength on cognitive performance, strawberry milkshake and super saccharin-reinforced animals were compared on a touchscreen visual discrimination task. Animals reinforced by strawberry milkshake were significantly faster to acquire the discrimination than animals reinforced by super saccharin. Taken together, these results suggest that strawberry milkshake is superior to super saccharin for operant behavioral testing and further confirms that the application of response rate analysis to multiple ratio tasks is a highly sensitive method for the detection of behavioral differences relevant to learning and motivation.
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13
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Schaefer N, Rotermund C, Blumrich EM, Lourenco MV, Joshi P, Hegemann RU, Jamwal S, Ali N, García Romero EM, Sharma S, Ghosh S, Sinha JK, Loke H, Jain V, Lepeta K, Salamian A, Sharma M, Golpich M, Nawrotek K, Paidi RK, Shahidzadeh SM, Piermartiri T, Amini E, Pastor V, Wilson Y, Adeniyi PA, Datusalia AK, Vafadari B, Saini V, Suárez-Pozos E, Kushwah N, Fontanet P, Turner AJ. The malleable brain: plasticity of neural circuits and behavior - a review from students to students. J Neurochem 2017. [PMID: 28632905 DOI: 10.1111/jnc.14107] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on page 788. Cover Image for this issue: doi: 10.1111/jnc.13815.
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Affiliation(s)
- Natascha Schaefer
- Institute for Clinical Neurobiology, Julius-Maximilians-University of Wuerzburg, Würzburg, Germany
| | - Carola Rotermund
- German Center of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany
| | - Eva-Maria Blumrich
- Centre for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, Bremen, Germany.,Centre for Environmental Research and Sustainable Technology, University of Bremen, Bremen, Germany
| | - Mychael V Lourenco
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pooja Joshi
- Inserm UMR 1141, Robert Debre Hospital, Paris, France
| | - Regina U Hegemann
- Department of Psychology, Brain Health Research Centre, University of Otago, Dunedin, New Zealand
| | - Sumit Jamwal
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Nilufar Ali
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | | | - Sorabh Sharma
- Neuropharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, India
| | - Shampa Ghosh
- National Institute of Nutrition (NIN), Indian Council of Medical Research (ICMR), Tarnaka, Hyderabad, India
| | - Jitendra K Sinha
- National Institute of Nutrition (NIN), Indian Council of Medical Research (ICMR), Tarnaka, Hyderabad, India
| | - Hannah Loke
- Hudson Institute of Medical Research, Melbourne, Victoria, Australia.,Department of Molecular and Translational Science, Monash University, Melbourne, Victoria, Australia
| | - Vishal Jain
- Defence Institute of Physiology and Allied Sciences, Delhi, India
| | - Katarzyna Lepeta
- Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Ahmad Salamian
- Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Mahima Sharma
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Mojtaba Golpich
- Department of Medicine, University Kebangsaan Malaysia Medical Centre (HUKM), Cheras, Kuala Lumpur, Malaysia
| | - Katarzyna Nawrotek
- Department of Process Thermodynamics, Faculty of Process and Environmental Engineering, Lodz University of Technology, Lodz, Poland
| | - Ramesh K Paidi
- CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India
| | - Sheila M Shahidzadeh
- Department of Biology, Program in Neuroscience, Syracuse University, Syracuse, New York, USA
| | - Tetsade Piermartiri
- Programa de Pós-Graduação em Neurociências, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
| | - Elham Amini
- Department of Medicine, University Kebangsaan Malaysia Medical Centre (HUKM), Cheras, Kuala Lumpur, Malaysia
| | - Veronica Pastor
- Instituto de Biología Celular y Neurociencia Prof. Eduardo De Robertis, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Yvette Wilson
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | - Philip A Adeniyi
- Cell Biology and Neurotoxicity Unit, Department of Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado - Ekiti, Ekiti State, Nigeria
| | | | - Benham Vafadari
- Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Vedangana Saini
- Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Edna Suárez-Pozos
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Toxicología, México
| | - Neetu Kushwah
- Defence Institute of Physiology and Allied Sciences, Delhi, India
| | - Paula Fontanet
- Division of Molecular and Cellular Neuroscience, Institute of Cellular Biology and Neuroscience (IBCN), CONICET-UBA, School of Medicine, Buenos Aires, Argentina
| | - Anthony J Turner
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK
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14
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Kim EW, Phillips BU, Heath CJ, Cho SY, Kim H, Sreedharan J, Song HT, Lee JE, Bussey TJ, Kim CH, Kim E, Saksida LM. Optimizing reproducibility of operant testing through reinforcer standardization: identification of key nutritional constituents determining reward strength in touchscreens. Mol Brain 2017; 10:31. [PMID: 28716096 PMCID: PMC5512767 DOI: 10.1186/s13041-017-0312-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 07/01/2017] [Indexed: 11/22/2022] Open
Abstract
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.
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Affiliation(s)
- Eun Woo Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, BK21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Benjamin U Phillips
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK
| | - Christopher J Heath
- School of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
| | - So Yeon Cho
- Department of Psychiatry, Institute of Behavioral Science in Medicine, BK21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Hyunjeong Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, BK21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Jemeen Sreedharan
- The Babraham Institute, Cambridge, CB22 3AT, UK.,Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 5 Cutcombe Road, London, SE5 9RT, UK
| | - Ho-Taek Song
- Department of Radiology, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Jong Eun Lee
- Department of Anatomy, BK21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Timothy J Bussey
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.,Molecular Medicine Research Laboratories, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The Brain and Mind Institute, Western University, London, ON, Canada
| | - Chul Hoon Kim
- Department of Pharmacology, BK21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul, 03722, Republic of Korea.
| | - Eosu Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, BK21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul, 03722, Republic of Korea. .,Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.
| | - Lisa M Saksida
- Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK.,Molecular Medicine Research Laboratories, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The Brain and Mind Institute, Western University, London, ON, Canada
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15
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Simpson EH, Kellendonk C. Insights About Striatal Circuit Function and Schizophrenia From a Mouse Model of Dopamine D 2 Receptor Upregulation. Biol Psychiatry 2017; 81:21-30. [PMID: 27720388 PMCID: PMC5121031 DOI: 10.1016/j.biopsych.2016.07.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Revised: 07/08/2016] [Accepted: 07/10/2016] [Indexed: 01/24/2023]
Abstract
The dopamine hypothesis of schizophrenia is supported by a large number of imaging studies that have identified an increase in dopamine binding at the D2 receptor selectively in the striatum. We review a decade of work using a regionally restricted and temporally regulated transgenic mouse model to investigate the behavioral, molecular, electrophysiological, and anatomical consequences of selective D2 receptor upregulation in the striatum. These studies have identified new and potentially important biomarkers at the circuit and molecular level that can now be explored in patients with schizophrenia. They provide an example of how animal models and their detailed level of neurobiological analysis allow a deepening of our understanding of the relationship between neuronal circuit function and symptoms of schizophrenia, and as a consequence generate new hypotheses that are testable in patients.
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Affiliation(s)
- Eleanor H. Simpson
- Department of Psychiatry, Columbia University,Neurobiology and Behavior, New York State Psychiatric Institute,Corresponding author: Eleanor H. Simpson, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 87, New York, New York 10032, , +1-646-774-6835
| | - Christoph Kellendonk
- Department of Pharmacology, Columbia University,Molecular Therapeutics, New York State Psychiatric Institute
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16
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Hantula DA. Expanding the Scope: Beyond the Familiar and Beyond the Page. THE BEHAVIOR ANALYST 2016; 39:189-196. [PMID: 31976940 DOI: 10.1007/s40614-016-0078-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Donald A Hantula
- Department of Psychology, Weiss Hall, Temple University, 1701 N 13 St, Philadelphia, PA 19122-6085 USA
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17
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Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area. Proc Natl Acad Sci U S A 2015; 112:E1498-506. [PMID: 25675529 DOI: 10.1073/pnas.1500450112] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.
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18
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Methods for Dissecting Motivation and Related Psychological Processes in Rodents. Curr Top Behav Neurosci 2015; 27:451-70. [PMID: 26272262 DOI: 10.1007/7854_2015_380] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Motivational impairments are increasingly recognized as being critical to functional deficits and decreased quality of life in patients diagnosed with psychiatric disease. Accordingly, much preclinical research has focused on identifying psychological and neurobiological processes which underlie motivation . Inferring motivation from changes in overt behavioural responding in animal models, however, is complicated, and care must be taken to ensure that the observed change is accurately characterized as a change in motivation , and not due to some other, task-related process. This chapter discusses current methods for assessing motivation and related psychological processes in rodents. Using an example from work characterizing the motivational impairments in an animal model of the negative symptoms of schizophrenia, we highlight the importance of careful and rigorous experimental dissection of motivation and the related psychological processes when characterizing motivational deficits in rodent models . We suggest that such work is critical to the successful translation of preclinical findings to therapeutic benefits for patients.
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19
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Millan MJ, Fone K, Steckler T, Horan WP. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur Neuropsychopharmacol 2014; 24:645-92. [PMID: 24820238 DOI: 10.1016/j.euroneuro.2014.03.008] [Citation(s) in RCA: 251] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 03/19/2014] [Indexed: 12/11/2022]
Abstract
Schizophrenia is a complex and multifactorial disorder generally diagnosed in young adults at the time of the first psychotic episode of delusions and hallucinations. These positive symptoms can be controlled in most patients by currently-available antipsychotics. Conversely, they are poorly effective against concomitant neurocognitive dysfunction, deficits in social cognition and negative symptoms (NS), which strongly contribute to poor functional outcome. The precise notion of NS has evolved over the past century, with recent studies - underpinned by novel rating methods - suggesting two major sub-domains: "decreased emotional expression", incorporating blunted affect and poverty of speech, and "avolition", which embraces amotivation, asociality and "anhedonia" (inability to anticipate pleasure). Recent studies implicate a dysfunction of frontocortico-temporal networks in the aetiology of NS, together with a disruption of cortico-striatal circuits, though other structures are also involved, like the insular and parietal cortices, amygdala and thalamus. At the cellular level, a disruption of GABAergic-glutamatergic balance, dopaminergic signalling and, possibly, oxytocinergic and cannibinoidergic transmission may be involved. Several agents are currently under clinical investigation for the potentially improved control of NS, including oxytocin itself, N-Methyl-d-Aspartate receptor modulators and minocycline. Further, magnetic-electrical "stimulation" strategies to recruit cortical circuits and "cognitive-behavioural-psychosocial" therapies likewise hold promise. To acquire novel insights into the causes and treatment of NS, experimental study is crucial, and opportunities are emerging for improved genetic, pharmacological and developmental modelling, together with more refined readouts related to deficits in reward, sociality and "expression". The present article comprises an integrative overview of the above issues as a platform for this Special Issue of European Neuropsychopharmacology in which five clinical and five preclinical articles treat individual themes in greater detail. This Volume provides, then, a framework for progress in the understanding - and ultimately control - of the debilitating NS of schizophrenia.
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Affiliation(s)
- Mark J Millan
- Pole of Innovation in Neuropsychiatry, Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, Paris, France.
| | - Kevin Fone
- School of Biomedical Sciences, Medical School, Queen׳s Medical Centre, Nottingham University, Nottingham NG72UH, UK
| | - Thomas Steckler
- Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium
| | - William P Horan
- VA Greater Los Angeles Healthcare System, University of California, Los Angeles, MIRECC 210A, Bldg. 210, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA
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20
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Markou A, Salamone JD, Bussey TJ, Mar AC, Brunner D, Gilmour G, Balsam P. Measuring reinforcement learning and motivation constructs in experimental animals: relevance to the negative symptoms of schizophrenia. Neurosci Biobehav Rev 2013; 37:2149-65. [PMID: 23994273 PMCID: PMC3849135 DOI: 10.1016/j.neubiorev.2013.08.007] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Revised: 08/12/2013] [Accepted: 08/16/2013] [Indexed: 10/26/2022]
Abstract
The present review article summarizes and expands upon the discussions that were initiated during a meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS; http://cntrics.ucdavis.edu) meeting. A major goal of the CNTRICS meeting was to identify experimental procedures and measures that can be used in laboratory animals to assess psychological constructs that are related to the psychopathology of schizophrenia. The issues discussed in this review reflect the deliberations of the Motivation Working Group of the CNTRICS meeting, which included most of the authors of this article as well as additional participants. After receiving task nominations from the general research community, this working group was asked to identify experimental procedures in laboratory animals that can assess aspects of reinforcement learning and motivation that may be relevant for research on the negative symptoms of schizophrenia, as well as other disorders characterized by deficits in reinforcement learning and motivation. The tasks described here that assess reinforcement learning are the Autoshaping Task, Probabilistic Reward Learning Tasks, and the Response Bias Probabilistic Reward Task. The tasks described here that assess motivation are Outcome Devaluation and Contingency Degradation Tasks and Effort-Based Tasks. In addition to describing such methods and procedures, the present article provides a working vocabulary for research and theory in this field, as well as an industry perspective about how such tasks may be used in drug discovery. It is hoped that this review can aid investigators who are conducting research in this complex area, promote translational studies by highlighting shared research goals and fostering a common vocabulary across basic and clinical fields, and facilitate the development of medications for the treatment of symptoms mediated by reinforcement learning and motivational deficits.
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Affiliation(s)
- Athina Markou
- Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive, M/C0603, La Jolla, CA 92093-0603, USA.
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21
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Jensen G, Ward RD, Balsam PD. Information: theory, brain, and behavior. J Exp Anal Behav 2013; 100:408-31. [PMID: 24122456 DOI: 10.1002/jeab.49] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 08/26/2013] [Indexed: 01/15/2023]
Abstract
In the 65 years since its formal specification, information theory has become an established statistical paradigm, providing powerful tools for quantifying probabilistic relationships. Behavior analysis has begun to adopt these tools as a novel means of measuring the interrelations between behavior, stimuli, and contingent outcomes. This approach holds great promise for making more precise determinations about the causes of behavior and the forms in which conditioning may be encoded by organisms. In addition to providing an introduction to the basics of information theory, we review some of the ways that information theory has informed the studies of Pavlovian conditioning, operant conditioning, and behavioral neuroscience. In addition to enriching each of these empirical domains, information theory has the potential to act as a common statistical framework by which results from different domains may be integrated, compared, and ultimately unified.
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22
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Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness. Proc Natl Acad Sci U S A 2013; 110:12462-7. [PMID: 23840059 DOI: 10.1073/pnas.1307925110] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH-seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxidative stress. Furthermore, deficits were observed in well-defined tests for the cognitive control of adaptive behavior using reversal learning and reinforcer devaluation paradigms. These deficits occurred even though DN-DISC1 mice showed intact performance in simple associative learning and normal responses in consumption of reward. In an additional series of assessments, motivational functions also were impoverished in DN-DISC1 mice, including tests of the dynamic modulation of reward value by effortful action, progressive ratio performance, and social behavior. Augmentation of an oxidative stress-associated cascade (e.g., a nuclear GAPDH cascade) points to an underlying condition that may contribute to the profile of cognitive and motivational impairments in DN-DISC1 mice by affecting the functional integrity of the prefrontal cortex and dysfunction within its connected networks. As such, this model should be useful for further preclinical research and drug discovery efforts relevant to the burden of prefrontal dysfunction in neuropsychiatric illness.
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23
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O'Tuathaigh CMP, Moran PM, Waddington JL. Genetic models of schizophrenia and related psychotic disorders: progress and pitfalls across the methodological "minefield". Cell Tissue Res 2013; 354:247-57. [PMID: 23715722 DOI: 10.1007/s00441-013-1652-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 04/29/2013] [Indexed: 12/13/2022]
Abstract
The challenge of modelling a complex and multifaceted disorder such as schizophrenia is epitomised by the considerable degree of phenotypic variability described in patients and by the absence of specific and consistent neuropathological biomarkers. The pattern and severity of a range of clinical features, including florid psychotic symptoms such as hallucinations and delusions, negative symptoms and cognitive dysfunction, together with age at onset, course of illness and other indices, can vary greatly between individual patients. The undefined nature of the relationship between diagnosis and underlying aetiology has complicated research in the field of clinical and preclinical neuroscience, thereby making it difficult to generate or evaluate appropriate disease models of schizophrenia. In the present review, we explore those conceptual and practical issues that relate specifically to the genetic modelling of schizophrenia and related disorders in rodents. Practical issues that impact on the robustness of endophenotypic findings and their translational relevance are discussed with reference to evidence from selective genetic models of candidate risk genes and copy number variants implicated in schizophrenia.
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Affiliation(s)
- Colm M P O'Tuathaigh
- School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland,
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24
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Bult CJ. Bioinformatics resources for behavior studies in the laboratory mouse. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2013. [PMID: 23195312 DOI: 10.1016/b978-0-12-398323-7.00004-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2023]
Abstract
This chapter focuses on two database resources that can facilitate the use of the laboratory mouse for genetic and genomic studies of behavior. The Mouse Phenome Database (MPD) contains baseline measurement data for a wide variety of phenotypes in inbred strains of mice and commonly used reference populations. MPD also supports tools for the visualization and statistical analysis of phenotype data. The Mouse Genome Informatics (MGI) database is a comprehensive resource for genetics and genomics of the laboratory mouse. MGI collects and integrates information about function, phenotype, disease associations, and developmental gene expression for all genome features in the laboratory mouse.
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25
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Leung LC, Wang GX, Mourrain P. Imaging zebrafish neural circuitry from whole brain to synapse. Front Neural Circuits 2013; 7:76. [PMID: 23630470 PMCID: PMC3634052 DOI: 10.3389/fncir.2013.00076] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 04/03/2013] [Indexed: 12/20/2022] Open
Abstract
Recent advances in imaging tools are inspiring zebrafish researchers to tackle ever more ambitious questions in the neurosciences. Behaviorally fundamental conserved neural networks can now be potentially studied using zebrafish from a brain-wide scale to molecular resolution. In this perspective, we offer a roadmap by which a zebrafish researcher can navigate the course from collecting neural activities across the brain associated with a behavior, to unraveling molecular identities and testing the functional relevance of active neurons. In doing so, important insights will be gained as to how neural networks generate behaviors and assimilate changes in synaptic connectivity.
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Affiliation(s)
- Louis C Leung
- Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences, Beckman Center, Stanford University Palo Alto, CA, USA
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26
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Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function. Proc Natl Acad Sci U S A 2013; 110:6583-8. [PMID: 23576723 DOI: 10.1073/pnas.1217665110] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a microRNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in long-term potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient microRNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.
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Kahn JB, Ward RD, Kahn LW, Rudy NM, Kandel ER, Balsam PD, Simpson EH. Medial prefrontal lesions in mice impair sustained attention but spare maintenance of information in working memory. Learn Mem 2012; 19:513-7. [PMID: 23073640 DOI: 10.1101/lm.026302.112] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Working memory and attention are complex cognitive functions that are disrupted in several neuropsychiatric disorders. Mouse models of such human diseases are commonly subjected to maze-based tests that can neither distinguish between these cognitive functions nor isolate specific aspects of either function. Here, we have adapted a simple visual discrimination task, and by varying only the timing of events within the same task construct, we are able to measure independently the behavioral response to increasing attentional demand and increasing length of time that information must be maintained in working memory. We determined that mPFC lesions in mice impair attention but not working memory maintenance.
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Affiliation(s)
- Julia B Kahn
- Department of Psychiatry, Columbia University, New York, New York 10032, USA
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Featherstone RE, Liang Y, Saunders JA, Tatard-Leitman VM, Ehrlichman RS, Siegel SJ. Subchronic ketamine treatment leads to permanent changes in EEG, cognition and the astrocytic glutamate transporter EAAT2 in mice. Neurobiol Dis 2012; 47:338-46. [DOI: 10.1016/j.nbd.2012.05.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 04/09/2012] [Accepted: 05/11/2012] [Indexed: 01/11/2023] Open
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Dichter GS, Damiano CA, Allen JA. Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings. J Neurodev Disord 2012; 4:19. [PMID: 22958744 PMCID: PMC3464940 DOI: 10.1186/1866-1955-4-19] [Citation(s) in RCA: 213] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Accepted: 05/02/2012] [Indexed: 02/07/2023] Open
Abstract
This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette's syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader-Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.
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Affiliation(s)
- Gabriel S Dichter
- Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Psychiatry, University of North Carolina School of Medicine, CB# 7255, 101 Manning Drive, Chapel Hill, NC, 275997255, USA
| | - Cara A Damiano
- Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - John A Allen
- Neuroscience Research Unit Pfizer Global Research and Development, Groton, CT 06340, USA
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Behavioral validation of avolition in schizophrenia. Schizophr Res 2012; 138:255-61. [PMID: 22398126 DOI: 10.1016/j.schres.2012.02.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 02/09/2012] [Accepted: 02/14/2012] [Indexed: 11/23/2022]
Abstract
BACKGROUND Since Kraepelin, avolition, a core symptom of schizophrenia, has been defined as a decrease in spontaneous, self-initiated and purposeful behaviors observed in daily life activities. However, the concurrent validity of commonly-used avolition measures has not been studied, and direct observation may offer a more objective way to measure avolition. METHOD A direct observation measure of spontaneous and self-initiated behaviors that can be observed in an inpatient setting was defined with the use of time sampling method. This direct observation measure was used with fifty inpatients with schizophrenia. Additionally, patients were asked to rate their current interest in and their level of engagement in 10 active behaviors during the preceding 7 days. Clinicians rated the patients' engagement in the same activities for the preceding 7 days as well. RESULTS The direct observation measure showed very good psychometric properties. Three clinical negative symptom scales showed moderate to high correlation with the direct measure. Concerning the retrospective ratings, patients' self-assessments were poorly correlated with clinicians' ratings, but showed high correlation with their subjective interests. CONCLUSIONS Clinical rating scales of negative symptoms show moderate to good concurrent validity as measures of avolition in schizophrenia. However, patients' self-reports do not appear to provide valid indices of avolition. Our results favor clinical negative symptoms scales that use observers' reports only, over patients' self-reports. The direct observation of patients' behavior offers a precise and objective measure of avolition that may be useful in drug challenges and clinical trials.
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Dissociation of hedonic reaction to reward and incentive motivation in an animal model of the negative symptoms of schizophrenia. Neuropsychopharmacology 2012; 37:1699-707. [PMID: 22414818 PMCID: PMC3358738 DOI: 10.1038/npp.2012.15] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
We previously showed that mice that selectively and reversibly overexpress striatal D2 receptors (D2R-OE) model the negative symptoms of schizophrenia. Specifically, D2R-OE mice display a deficit in incentive motivation. The present studies investigated the basis for this deficit. First, we assessed whether hedonic reaction to reward is intact in D2R-OE mice. We assessed licking behavior and video-scored positive hedonic facial reactions to increasing concentrations of sucrose in control and D2R-OE mice. We found no difference between D2R-OE mice and controls in hedonic reactions. To further understand the basis of the motivational deficit, mice were given a choice between pressing a lever for access to a preferred reward (evaporated milk) or consuming a freely available less preferred reward (home-cage chow). D2R-OE mice pressed less for the preferred milk and consumed more of the freely available less preferred chow, indicating that striatal overexpression of postsynaptic D2Rs can alter cost/benefit computations, leading to a motivational deficit. This motivational impairment was ameliorated when the transgene was turned off and D2R levels were normalized. Such a deficit may arise from impaired ability to represent the value of future rewards. To test this, we used operant concurrent schedules and found reduced sensitivity to the value of future outcomes in D2R-OE mice. These results demonstrate for the first time in a transgenic animal model of schizophrenia a dissociation between hedonic reaction to reward and incentive motivation, and show a striking parallel to the proposed neurobiological and psychological mechanisms of impaired incentive motivation in schizophrenia.
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Abstract
Cancer therapy makes patients sick. The therapies that are available to clinicians allow them to successfully control nausea, emesis and pain. However, this is not the case for a number of other symptoms that include fatigue, distractibility, poor memory, and diminished interest in previously pleasurable activities. These symptoms cluster during the course of cancer therapy and impair patient quality of life, limit therapy options and do not always resolve at the cessation of treatment. It is possible to describe the intensity and temporal features of symptoms and assess their relationship with the inflammatory response that is associated with cancer and cancer therapy. At the preclinical level, sophisticated animal models still need to be deployed to study the causal role of inflammation in specific components of cancer-related symptoms. Various approaches can be optimally combined in a translational symptom research pathway to provide a framework for assessing in a systematic manner the neurobehavioral toxicity of existing and newly developed cancer therapies. Ultimately, this knowledge will allow derivation of mechanism-based interventions to prevent or alleviate cancer-related symptoms.
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