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Handling method alters the hedonic value of reward in laboratory mice.

ABSTRACT: Mice are the most widely used model species for drug discovery and scientific research. Consequently, it is important to refine laboratory procedures and practices to ensure high standards of welfare and scientific data quality. Recent studies have identified that the standard practice of handling laboratory mice by their tails increases behaviours indicative of anxiety, which can be overcome by handling mice using a tunnel. However, despite clear negative effects on mice's behaviour, tunnel handling has yet to be widely implemented. In this study, we provide the first evidence that tail handling also reduces mice's responses to reward. Anhedonia is a core symptom of clinical depression, and is measured in rodents by assessing how they consume a sucrose solution: depressed mice consume less sucrose and the size of their licking bouts when drinking (their 'lick cluster sizes') also tend to be smaller. We found that tail handled mice showed more anhedonic responses in both measures compared to tunnel handled mice, indicative of a decreased responsiveness to reward and potentially a more depressive-like state. Our findings have significant implications for the welfare of laboratory mice as well as the design and interpretation of scientific studies, particularly those investigating or involving reward.

SUBMITTER: Clarkson JM

PROVIDER: S-EPMC5799408 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Handling method alters the hedonic value of reward in laboratory mice.

Clarkson Jasmine M JM Dwyer Dominic M DM Flecknell Paul A PA Leach Matthew C MC Rowe Candy C

Scientific reports 20180205 1

Mice are the most widely used model species for drug discovery and scientific research. Consequently, it is important to refine laboratory procedures and practices to ensure high standards of welfare and scientific data quality. Recent studies have identified that the standard practice of handling laboratory mice by their tails increases behaviours indicative of anxiety, which can be overcome by handling mice using a tunnel. However, despite clear negative effects on mice's behaviour, tunnel han ...[more]

PMID: 29402923

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Project description:Handling of laboratory mice is essential for experiments and husbandry, but handling can increase anxiety in mice, compromising their welfare and potentially reducing replicability between studies. The use of non-aversive handling (e.g., tunnel handling or cupping), rather than the standard method of picking mice up by the tail, has been shown to enhance interaction with a handler, reduce anxiety-like behaviours, and increase exploration and performance in standard behavioural tests. Despite this, some labs continue to use tail handling for routine husbandry, and the extent to which non-aversive methods are being used is currently unknown. Here we conducted an international online survey targeting individuals that work with and/or conduct research using laboratory mice. The survey aimed to identify the handling methods currently being used, and to determine common obstacles that may be preventing the wider uptake of non-aversive handling. We also surveyed opinions concerning the current data in support of non-aversive handling for mouse welfare and scientific outcomes. 390 complete responses were received and analysed quantitatively and thematically. We found that 35% report using tail handling only, and 43% use a combination of tail and non-aversive methods. 18% of respondents reported exclusively using non-aversive methods. The vast majority of participants were convinced that non-aversive handling improves animal welfare and scientific outcomes. However, the survey indicated that researchers were significantly less likely to have heard of non-aversive handling and more likely to use tail handling compared with animal care staff. Thematic analysis revealed there were concerns regarding the time required for non-aversive methods compared with tail handling, and that there was a perceived incompatibility of tunnel handling with restraint, health checks and other routine procedures. Respondents also highlighted a need for additional research into the impact of handling method that is representative of experimental protocols and physiological indicators used in the biomedical fields. This survey highlights where targeted research, outreach, training and funding may have the greatest impact on increasing uptake of non-aversive handling methods for laboratory mice.

Project description:Abnormal reward processing is a hallmark of neurodegenerative diseases, most strikingly in frontotemporal dementia. However, the phenotypic repertoire and neuroanatomical substrates of abnormal reward behaviour in these diseases remain incompletely characterized and poorly understood. Here we addressed these issues in a large, intensively phenotyped patient cohort representing all major syndromes of sporadic frontotemporal dementia and Alzheimer's disease. We studied 27 patients with behavioural variant frontotemporal dementia, 58 with primary progressive aphasia (22 semantic variant, 24 non-fluent/agrammatic variant and 12 logopenic) and 34 with typical amnestic Alzheimer's disease, in relation to 42 healthy older individuals. Changes in behavioural responsiveness were assessed for canonical primary rewards (appetite, sweet tooth, sexual activity) and non-primary rewards (music, religion, art, colours), using a semi-structured survey completed by patients' primary caregivers. Changes in more general socio-emotional behaviours were also recorded. We applied multiple correspondence analysis and k-means clustering to map relationships between hedonic domains and extract core factors defining aberrant hedonic phenotypes. Neuroanatomical associations were assessed using voxel-based morphometry of brain MRI images across the combined patient cohort. Altered (increased and/or decreased) reward responsiveness was exhibited by most patients in the behavioural and semantic variants of frontotemporal dementia and around two-thirds of patients in other dementia groups, significantly (P < 0.05) more frequently than in healthy controls. While food-directed changes were most prevalent across the patient cohort, behavioural changes directed toward non-primary rewards occurred significantly more frequently (P < 0.05) in the behavioural and semantic variants of frontotemporal dementia than in other patient groups. Hedonic behavioural changes across the patient cohort were underpinned by two principal factors: a 'gating' factor determining the emergence of altered reward behaviour and a 'modulatory' factor determining how that behaviour is directed. These factors were expressed jointly in a set of four core, trans-diagnostic and multimodal hedonic phenotypes: 'reward-seeking', 'reward-restricted', 'eating-predominant' and 'control-like'-variably represented across the cohort and associated with more pervasive socio-emotional behavioural abnormalities. The principal gating factor was associated (P < 0.05 after correction for multiple voxel-wise comparisons over the whole brain) with a common profile of grey matter atrophy in anterior cingulate, bilateral temporal poles, right middle frontal and fusiform gyri: the cortical circuitry that mediates behavioural salience and semantic and affective appraisal of sensory stimuli. Our findings define a multi-domain phenotypic architecture for aberrant reward behaviours in major dementias, with novel implications for the neurobiological understanding and clinical management of these diseases.

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Handling method alters the hedonic value of reward in laboratory mice.

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Handling method alters the hedonic value of reward in laboratory mice.

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