Design of composite measure schemes for comparative severity assessment in animal-based neuroscience research: A case study focussed on rat epilepsy models

Dijk, Roelof Maarten van; Koska, Ines; Bleich, André; Tolba, René; Seiffert, Isabel; Möller, Christina; Liberto, Valentina Di; Talbot, Steven R.; Potschka, Heidrun

doi:10.1371/journal.pone.0230141

Cited by 17 publications

(34 citation statements)

References 38 publications

(81 reference statements)

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“…In terms of welfare, there is growing evidence that multimodal analysis is a more valuable approach towards evidence-based assessment of severity in laboratory animals [ 95 – 97 ]. In this study, we focused on burrowing and could not find differences between the groups besides the short-term decrease directly after resocialization.…”

Section: Discussionmentioning

confidence: 99%

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

et al. 2020

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Early life stress compromises brain development and can contribute to the development of mental illnesses. A common animal model used to study different facets of psychiatric disorders is social isolation from early life on. In rats, this isolation can induce long-lasting alterations in molecular expression and in behavior. Since social isolation models severe psychiatric symptoms, it is to be expected that it affects the overall wellbeing of the animals. As also promoted by the 3Rs principle, though, it is pivotal to decrease the burden of laboratory animals by limiting the number of subjects (reduce, replace) and by improving the animals’ wellbeing (refine). The aim of this study was therefore to test possible refinement strategies such as resocialization and mere adult social isolation. We examined whether the alternatives still triggered the necessary phenotype while minimizing the stress load on the animals. Interestingly, we did not find reduced wellbeing-associated burrowing performance in isolated rats. The hyperactive phenotype seen in socially isolated animals was observed for rats undergoing the adult-only isolation, but resocializing ameliorated the locomotor abnormality. Isolation strongly affected markers of neuroplasticity in the prefrontal cortex independent of timing: mRNA levels of Arc , Bdnf and the pool of Bdnf transcripts with the 3’ long UTR were reduced in all groups. Bdnf splice variant IV expression was reduced in lifelong-isolated animals. Some of these deficits normalized after resocialization; likewise, exon VI Bdnf mRNA levels were reduced only in animals persistently isolated. Conversely, social deprivation did not affect the expression of Gad67 and Pvb , two GABAergic markers, whereas changes occurred in the expression of dopamine d1 and d2 receptors. As adult isolation was sufficient to trigger the hyperactive phenotype and impaired neuroplasticity in the prefrontal cortex, it could be a candidate for a refinement strategy for certain research questions. To fully grade the severity of post-weaning social isolation and the alternatives, adult isolation and resocialization, a more profound and multimodal assessment approach is necessary.

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Section: Discussionmentioning

confidence: 99%

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

et al. 2020

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“…First, the selection of an appropriate animal model needs to consider the scientific aims of a study. However, whenever different alternate options meet the respective requirements, an animalwelfare based prioritization of models should be intensely considered from an ethical point of view for the choice of the model [24,25]. Therefore, it is of particular relevance to determine and compare the severity of different experimental models, and to assess possible refinement measures in an evidence-based manner.…”

Section: Discussionmentioning

confidence: 99%

Toward evidence-based severity assessment in mouse models with repeated seizures: I. Electrical kindling

Boldt

Koska

Dijk

et al. 2021

Epilepsy & Behavior

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Objective: Ethical decisions about an allowance for animal experiments need to be based on scientifically sound information about the burden and distress associated with the experimental procedure and models. Thereby, species differences need to be considered for recommendations regarding evidence-based severity assessment and refinement measures. Methods: A comprehensive analysis of behavioral patterns and corticosterone or its metabolites in serum and feces was completed in kindled mice. The impact of kindling via two different stimulation sites in the amygdala and hippocampus was determined. Data were compared to those from naive and electrodeimplanted groups. Results: Amygdala and hippocampus kindled mice exhibited comparable behavioral patterns with increased activity in the open field, reduced anxiety-associated behavior in the elevated-plus maze, and increased anhedonia-associated behavior in the saccharin preference test. In addition, repeated stimulation of the hippocampus caused a reduction in burrowing behavior and an increase in active social interaction. Levels of corticosterone and its metabolites were not altered in serum or feces, respectively. A comparison of mouse data with findings from amygdala kindled rats confirmed pronounced species differences in behavioral patterns associated with the kindling process. Significance: Taken together the findings suggest a severity classification for the mouse kindling paradigms as moderate regardless of the stimulation site. The outcome of the species comparison provides valuable guidance for species selection for studies exploring behavioral comorbidities. In this context, it is emphasized that the mouse kindling paradigms seem to be well suited for studies exploring the link between ictal events and network alterations on the one hand, and hyperactivity and anhedoniaassociated behavior on the other hand. Moreover, the underlying pathophysiological mechanisms and the impact of therapeutic interventions on these behavioral alterations can be studied in these paradigms providing guidance for the clinical management of respective psychiatric comorbidities in patients.

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“…The parameters of interest have been selected based on consortium data, which were obtained in adult rodent disease models, and which supported an informative value for the purpose of severity assessment (e.g. 8 , 9 , 12 – 20 ). Information about model-specific characteristics provide key elements for an evidence-based grading of severity, and allow filling of gaps in model-specific refinement recommendations 8 .…”

Section: Discussionmentioning

confidence: 99%

“…The applied candidate composite measure scheme was based on a comprehensive consortium data set for assessing and classifying severity in different adult rodent animal models 8 . Parameters with a high informative value were selected based on a bioinformatic approach among others comprising principal component analyses identifying the parameters best distinguishing between experimental and control animals and cross-correlation analyses guiding the selection of parameters with added value 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Development of behavioral patterns in young C57BL/6J mice: a home cage-based study

Reiber

Koska

Pace

et al. 2022

Sci Rep

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Evidence exists that behavioral patterns only stabilize once mice reach adulthood. Detailed information about the course of behavioral patterns is of particular relevance for neuroscientific research and for the assessment of cumulative severity in genetically modified mice. The analysis considered five age groups focusing on behavioral assessments in the animals’ familiar home cage environment during the adolescence phase. We confirmed age- and sex-specific differences for several of the behavioral parameters and fecal corticosterone metabolites. Interestingly, an age-dependent decline in saccharin preference was detected in female mice. Regardless of sex, relevant levels of burrowing activity were only observed during later developmental phases. The development of nest complexity following the offer of new material was affected by age in female mice. In female and male mice, an age-dependency was evident for wheel running reaching a peak at P 50. A progressive increase with age was also observed for Open field activity. The data sets provide guidance for behavioral studies and for development of composite measure schemes for evidence-based severity assessment in young mice. Except for the burrowing test, the different behavioral tests can be applied in different age groups during post-weaning development. However, age- and sex-specific characteristics need to be considered.

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Design of composite measure schemes for comparative severity assessment in animal-based neuroscience research: A case study focussed on rat epilepsy models

Cited by 17 publications

References 38 publications

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity

Toward evidence-based severity assessment in mouse models with repeated seizures: I. Electrical kindling

Development of behavioral patterns in young C57BL/6J mice: a home cage-based study

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