Development and validation of a rodent touchscreen battery for assessing motivation and affective state
Lead Research Organisation:
University of Cambridge
Department Name: Psychology
Abstract
Mental illness currently contributes the highest global economic burden of all chronic diseases. Neurological disorders such as stroke and dementia also reflect a huge burden to society that is expected to increase as the population ages. Impaired motivation and emotional reactivity are core symptoms of these disorders, typically occurring early in the disease course and persisting or worsening as the illness progresses. These symptoms are particularly debilitating for both patients and their caregivers; for example, those caring for an Alzheimer's patient reported that these symptoms are more distressing than the memory loss primarily associated with the disease. However, at present, no targeted pharmacotherapies exist for these symptoms, suggesting that there is a great need for further research in this area.
Animal models are essential in the search for knowledge about, and in the development of new treatments for, these conditions. However, the way in which symptoms involving emotion and motivation are assessed in animals is often overly simplistic and differs greatly from how these symptoms are assessed in humans. For example, most current studies in this area investigate these aspects of behaviour using techniques that generate negative emotions in the animals (e.g., fear and anxiety) via inescapable electrical shock, restraint or immersion in water. This makes comparison to humans, and therefore the development of effective treatments, very difficult.
We have developed a touchscreen-based system that is now well-established for assessing learning, memory and attention in mice and rats. The tests simply require animals to nosepoke images on the screen with correct responses rewarded with a drop of milkshake. In this project we propose to develop an analogous touchscreen-based system for the assessment of emotion and motivation in rodents.
The development of a touchscreen-based system for the assessment of emotion and motivation will allow for the neurobiological investigation of these critical aspects of behaviour in a non-stressful fashion. The new methods will also allow us to measure the effectiveness of new drugs designed to alleviate the symptoms of negative emotion and lack of motivation seen in many human neuropsychiatric and neurodegenerative diseases without causing any distress to the animals involved. The touchscreen assessments are also designed to be very similar to those used in human clinical trials, which will increase the probability that a positive effect seen in the animals will translate to a positive effect in humans. Furthermore, this assessment system will be very useful for routine evaluation of animal welfare and also in determining if changes in husbandry techniques and housing environment lead to reduced stress, thereby allowing us to objectively improve the quality of life for animals in the laboratory more generally. Widespread adoption of touchscreen-based assays to assess emotion and motivation could substantially decrease the severity of testing for at least 30,000 rodents annually.
Animal models are essential in the search for knowledge about, and in the development of new treatments for, these conditions. However, the way in which symptoms involving emotion and motivation are assessed in animals is often overly simplistic and differs greatly from how these symptoms are assessed in humans. For example, most current studies in this area investigate these aspects of behaviour using techniques that generate negative emotions in the animals (e.g., fear and anxiety) via inescapable electrical shock, restraint or immersion in water. This makes comparison to humans, and therefore the development of effective treatments, very difficult.
We have developed a touchscreen-based system that is now well-established for assessing learning, memory and attention in mice and rats. The tests simply require animals to nosepoke images on the screen with correct responses rewarded with a drop of milkshake. In this project we propose to develop an analogous touchscreen-based system for the assessment of emotion and motivation in rodents.
The development of a touchscreen-based system for the assessment of emotion and motivation will allow for the neurobiological investigation of these critical aspects of behaviour in a non-stressful fashion. The new methods will also allow us to measure the effectiveness of new drugs designed to alleviate the symptoms of negative emotion and lack of motivation seen in many human neuropsychiatric and neurodegenerative diseases without causing any distress to the animals involved. The touchscreen assessments are also designed to be very similar to those used in human clinical trials, which will increase the probability that a positive effect seen in the animals will translate to a positive effect in humans. Furthermore, this assessment system will be very useful for routine evaluation of animal welfare and also in determining if changes in husbandry techniques and housing environment lead to reduced stress, thereby allowing us to objectively improve the quality of life for animals in the laboratory more generally. Widespread adoption of touchscreen-based assays to assess emotion and motivation could substantially decrease the severity of testing for at least 30,000 rodents annually.
Technical Summary
Motivation and emotional processing are compromised in numerous disorders (e.g., Alzheimer's disease, schizophrenia and depression) and thus are frequently assessed in rodent disease models. However, most current tests fall into the moderate severity band as they are highly aversive and involve restraint, inescapable electric shock or forced swimming.
The rodent touchscreen testing system is well-established as a versatile cognitive assessment tool that avoids aversive conditions, instead using rewards such as milkshake. We propose to develop a suite of rodent touchscreen-based assays for motivation and emotion and show that they can replace higher-severity assays (refinement) by validating their efficacy with a series of experiments focused on three manipulations known to affect different aspects of these constructs: (1) a standardised panel of drugs; (2) chronic exposure to the stress hormone corticosterone; and (3) ethologically-valid environmental manipulations. This will also demonstrate the utility of these tasks for assessing new drugs for benefits on emotional state, for measuring rodent stress and monitoring welfare, and for standardised assessment of new welfare manipulations such as environmental enrichment or changes in husbandry practises.
Aversive tasks to measure emotion and motivation are used extensively. Widespread adoption of touchscreen-based assays to assess emotion and motivation could decrease the severity of testing for at least 30,000 rodents annually. Touchscreen-based rodent tests are very similar to those used in humans, which greatly increases the probability of successful translation of treatments from the lab to the clinic, potentially reducing the number of animal experiments required. Additional advantages are increased precision of data through automation and computerisation and the possibility of conducting multiple tests in the same apparatus, both of which contribute to reduction.
The rodent touchscreen testing system is well-established as a versatile cognitive assessment tool that avoids aversive conditions, instead using rewards such as milkshake. We propose to develop a suite of rodent touchscreen-based assays for motivation and emotion and show that they can replace higher-severity assays (refinement) by validating their efficacy with a series of experiments focused on three manipulations known to affect different aspects of these constructs: (1) a standardised panel of drugs; (2) chronic exposure to the stress hormone corticosterone; and (3) ethologically-valid environmental manipulations. This will also demonstrate the utility of these tasks for assessing new drugs for benefits on emotional state, for measuring rodent stress and monitoring welfare, and for standardised assessment of new welfare manipulations such as environmental enrichment or changes in husbandry practises.
Aversive tasks to measure emotion and motivation are used extensively. Widespread adoption of touchscreen-based assays to assess emotion and motivation could decrease the severity of testing for at least 30,000 rodents annually. Touchscreen-based rodent tests are very similar to those used in humans, which greatly increases the probability of successful translation of treatments from the lab to the clinic, potentially reducing the number of animal experiments required. Additional advantages are increased precision of data through automation and computerisation and the possibility of conducting multiple tests in the same apparatus, both of which contribute to reduction.
Planned Impact
The 3Rs impact of this proposal will be apparent in terms of (i) refinement: some 30,000 laboratory rodents could undergo mild instead of moderate severity procedures annually and (ii) reduction: improved measures in rodents that are more similar to the tests used in humans could lead to more accurate data and better translation to the clinic, thereby necessitating fewer subsequent animal experiments.
Academic Beneficiaries
For this group, the primary 3Rs impact is reduction of severity of their emotion and motivation assays from moderate to mild (refinement). There are also further 3Rs impacts that are closely intertwined with scientific impacts, since better experimental designs and procedures lead to reduction. For example:
One animal can be evaluated on multiple assays in this apparatus, which increases the data yield per animal. This allows a within-subjects design, and reduces the number of animals required by up to 5-fold. This also allows for more robust evaluations of a particular construct due to the generation of distinct outputs from each of the assays that are relevant to the construct under study, thereby reducing noise and group sizes.
Automation (i) increases the number of variables recorded per animal; (ii) enhances measurement accuracy and prevents experimenter bias, which reduces noise and maximises the probability of detecting genuine effects; (iii) reduces the probability of procedural errors and handling-induced confounds that could necessitate experimental repetition and further animal use.
High face validity with human tests increases the likelihood of good translation from animal models to humans. This could lead to a higher rate of hits in drug discovery programmes, which would result in fewer animal experiments overall.
Researchers would benefit from being able to assess emotion and motivation in the same apparatus in which they assess cognition, which could reduce variability and improve the accuracy of their experiments.
Researchers could improve their cognitive assessments in rodent models by pre-screening and eliminating potential motivation-related confounds, thus reducing the overall number of animal experiments.
Researchers interested in laboratory animal welfare and animal care practices could use this system as a tool to standardize and monitor affective state and stress measurements, and thus improve living conditions for laboratory animals.
Other Beneficiaries
(1) ASPA-designated named persons, AWERB members and laboratory animal care staff will have mild severity alternatives to moderate severity assays, which they can promote to researchers at their institution. The project also offers a non-invasive and standardised method to assess laboratory animal welfare and how it is affected by changes to husbandry practices or other policies and procedures.
(2) Policy makers and public bodies could benefit from this work as it would contribute toward evidence-based policy making both from the perspective of disease management and also laboratory animal welfare and experimentation.
(3) Carers and individuals affected by diseases such as schizophrenia, dementia and Huntington's disease who are at high risk of experiencing disrupted motivation and affective processing would benefit from assays as they could yield novel therapeutics.
(4) The general public will find this work beneficial in that it demonstrates the value of behavioural neuroscience research in facilitating better understanding of and therapies for disease and provides an example of active engagement by the scientific community with the 3Rs to improve the welfare of laboratory animals involved in such research.
(5) Pharmaceutical Industry would benefit from the translational potential of these assays in their drug discovery programmes. This group would also have the potential to derive a significant economic impact if they use these assays to discover a successful novel therapeutic.
Academic Beneficiaries
For this group, the primary 3Rs impact is reduction of severity of their emotion and motivation assays from moderate to mild (refinement). There are also further 3Rs impacts that are closely intertwined with scientific impacts, since better experimental designs and procedures lead to reduction. For example:
One animal can be evaluated on multiple assays in this apparatus, which increases the data yield per animal. This allows a within-subjects design, and reduces the number of animals required by up to 5-fold. This also allows for more robust evaluations of a particular construct due to the generation of distinct outputs from each of the assays that are relevant to the construct under study, thereby reducing noise and group sizes.
Automation (i) increases the number of variables recorded per animal; (ii) enhances measurement accuracy and prevents experimenter bias, which reduces noise and maximises the probability of detecting genuine effects; (iii) reduces the probability of procedural errors and handling-induced confounds that could necessitate experimental repetition and further animal use.
High face validity with human tests increases the likelihood of good translation from animal models to humans. This could lead to a higher rate of hits in drug discovery programmes, which would result in fewer animal experiments overall.
Researchers would benefit from being able to assess emotion and motivation in the same apparatus in which they assess cognition, which could reduce variability and improve the accuracy of their experiments.
Researchers could improve their cognitive assessments in rodent models by pre-screening and eliminating potential motivation-related confounds, thus reducing the overall number of animal experiments.
Researchers interested in laboratory animal welfare and animal care practices could use this system as a tool to standardize and monitor affective state and stress measurements, and thus improve living conditions for laboratory animals.
Other Beneficiaries
(1) ASPA-designated named persons, AWERB members and laboratory animal care staff will have mild severity alternatives to moderate severity assays, which they can promote to researchers at their institution. The project also offers a non-invasive and standardised method to assess laboratory animal welfare and how it is affected by changes to husbandry practices or other policies and procedures.
(2) Policy makers and public bodies could benefit from this work as it would contribute toward evidence-based policy making both from the perspective of disease management and also laboratory animal welfare and experimentation.
(3) Carers and individuals affected by diseases such as schizophrenia, dementia and Huntington's disease who are at high risk of experiencing disrupted motivation and affective processing would benefit from assays as they could yield novel therapeutics.
(4) The general public will find this work beneficial in that it demonstrates the value of behavioural neuroscience research in facilitating better understanding of and therapies for disease and provides an example of active engagement by the scientific community with the 3Rs to improve the welfare of laboratory animals involved in such research.
(5) Pharmaceutical Industry would benefit from the translational potential of these assays in their drug discovery programmes. This group would also have the potential to derive a significant economic impact if they use these assays to discover a successful novel therapeutic.