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

Abstract

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.

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

“…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 .…”

“…Based on the promising candidate parameters, fully validated in adult rodent models (e.g. 9 , 12 – 15 , 17 ), we subsequently tested for applicability in young mice. Moreover, the compilation of tests considered aspects of animal welfare such as the ethical necessity of group housing, and also allows practical implication in the majority of conventional animal facilities.…”

Comparative Severity Assessment of Genetic, Stress-Based, and Pharmacological Mouse Models of Depression

“…Yet, the evaluation of suffering should be based on the animals’ state rather than anthropomorphic predictions. Hence, the severity assessment was based on established empirical measures of physiology and behavior ( Bleich and Tolba, 2017 ; Moller et al, 2018 ; Koska et al, 2019 ; Seiffert et al, 2019 ; Bleich et al, 2020 ; Jirkof et al, 2020 ; van Dijk et al, 2020 ; Boldt et al, 2021 ; Buchecker et al, 2022 ). Furthermore, we have chosen to use parameters that hardly interfere with the animals and, therefore, should not confound the results by additional stress, e.g., more elaborate behavioral tests like tests for anxiety-related behavior.…”

“…We investigated the preference for saccharin solution of the stress-based models as previously described ( Kronenberg et al, 2012 ; Klein et al, 2015 ; Boldt et al, 2021 ). Briefly, we determined the intake from two drinking bottles in 24 h on four consecutive days with either two bottles filled with water (day 1 and 3) or one with water and one with a 0.1% saccharin solution (day 2 and 4).…”

Phenotyping Young GluA1 Deficient Mice – A Behavioral Characterization in a Genetic Loss-of-Function Model

“…Among the parameters analyzed in the familiar environment of the mice, we examined the preference for saccharin, which we have previously introduced as a behavioral assay for severity assessment in laboratory rodents (e.g., Boldt et al, 2021). The innate preference for sweetness displayed by laboratory rodents can be considered to determine depression-related phenotypical traits (Crawley, 2006).…”