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Behavioral test battery. Over six consecutive days, mice were tested during their active period in a behavioral battery consisting of open‐field activity trial 1, light–dark box trial 1, elevated plus‐maze, open‐field activity trial 2, light–dark box trial 2, and novel object exploration test. Tests were conducted in the order of increasing invasiveness and the elevated plus‐maze was only conducted once to avoid the multiple test effect
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High and Low Activity strains of mice (displaying low and high anxiety‐like behavior, respectively) with 7.8‐20 fold differences in open‐field activity (OFA) were selected and subsequently inbred to use as a genetic model for studying anxiety‐like behavior in mice (DeFries et al., 1978, Behavior Genetics, 8:3‐13). These strains exhibited difference...
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... More recent work using these High and Low Activity strains included confirming the behavioral phenotypes of these strains, and whole genome sequencing to uncover genes and pathways contributing to the behavioral differences between these strains. Booher et al. (2021) used a behavioral test battery, previously mentioned, that confirmed the extreme anxiety-related behavioral differences between the High and Low Activity strains [20]. To address the previously raised concerns about activity level and general locomotion as possible confounding variables, the novel object test and home cage wheel running were added to the behavioral protocol. ...
... More recent work using these High and Low Activity strains included confirming the behavioral phenotypes of these strains, and whole genome sequencing to uncover genes and pathways contributing to the behavioral differences between these strains. Booher et al. (2021) used a behavioral test battery, previously mentioned, that confirmed the extreme anxiety-related behavioral differences between the High and Low Activity strains [20]. To address the previously raised concerns about activity level and general locomotion as possible confounding variables, the novel object test and home cage wheel running were added to the behavioral protocol. ...
... The male Low Activity mice ran almost twice as much daily compared to male High Activity. However, the female High and Low Activity mice did not differ in the amount of wheel running [20]. These new results provide support for the hypothesis that the behavioral differences observed between the High and Low Activity strains are not due to differences in overall movement. ...
Open-field activity is a commonly used measure of anxiety-related behavior in rodents. The inbred High and Low Activity strains of mice, selected for extreme differences in open-field activity, have been used as a genetic model of anxiety-related behaviors. These selected strains have been thoroughly studied through extensive behavioral testing, quantitative trait locus (QTL) mapping, whole-genome sequencing, and RNA sequencing, to uncover phenotypic and genotypic differences related to anxiety-related behavior. However, the effects of anxiolytic drugs on anxiety-related behavior in these strains have not been studied previously. This study allowed us to expand on previous findings to further characterize the anxiety-related behavior of these unique strains, using an anxiolytic drug. The goal of this study was to determine whether the treatment of adult male and female High Activity (low anxiety) and Low Activity (high anxiety) mice with diazepam, an agonist at the benzodiazepine allosteric site on the GABAA receptor and a drug commonly prescribed to treat anxiety disorders in humans, led to decreases in anxiety-like defensive behavioral responses as assessed in the open-field test (OFT) and elevated plus-maze (EPM). We tested the effects of three doses of diazepam (0, 0.5, 1.0, 3.0 mg/kg, i.p.), given 30 min before behavioral testing to one High Activity strain (H2) and two Low Activity strains (L1 and L2). There was an anxiolytic effect of diazepam observed in the High Activity strain, with more entries into the open arms of the elevated plus-maze, an effect similar to that seen in common mouse strains. However, the only anxiolytic effect of diazepam seen in the Low Activity strains was a reduction in stretch attend posture (SAP). Low Activity strains also displayed freezing behavior in both the OFT and EPM. The combination of the observed freezing behavior, that was not reduced by diazepam, and the reduction in SAP seen with diazepam, suggests a more complex phenotype that includes a component of innate fear in addition to anxiety-related risk assessment behaviors. Since fear and anxiety are distinguishable traits, and both contribute to human anxiety disorders, these results provide novel insight about interpretation of previous genetic and phenotypic differences observed between the High and Low Activity strains.
... 18 Following the original selection experiment, the lines were inbred to produce the six inbred DeFries strains: two high (H1 and H2), two low (L1 and L2) and two control lines (C1 and C2). More recently, we have 19 confirmed that the extreme differences in OFA remain over 40 years later. In addition to extreme OFA differences, the High (H2) Activity mice exhibited low anxiety-like behaviors and the Low (L2) Activity mice exhibited high anxiety-like behaviors in the light-dark box (LDB) and elevated plus-maze (EPM) paradigms, demonstrating continued support for their high and low anxiety-like behavioral selection. ...
... In addition to extreme OFA differences, the High (H2) Activity mice exhibited low anxiety-like behaviors and the Low (L2) Activity mice exhibited high anxiety-like behaviors in the light-dark box (LDB) and elevated plus-maze (EPM) paradigms, demonstrating continued support for their high and low anxiety-like behavioral selection. 19 A common concern about the use of the High and Low Activity mice as a model of anxiety-related behaviors is whether the differences observed in the behavioral tests are due merely to differences in locomotion in general. To test this concern, Booher et al. 19 also included novel object exploration, an anxiety-like behavioral measure that does not rely heavily on locomotion. ...
... 19 A common concern about the use of the High and Low Activity mice as a model of anxiety-related behaviors is whether the differences observed in the behavioral tests are due merely to differences in locomotion in general. To test this concern, Booher et al. 19 also included novel object exploration, an anxiety-like behavioral measure that does not rely heavily on locomotion. We also tested home cage voluntary wheel running in their behavioral battery. ...
High and Low Activity strains of mice were bidirectionally selected for differences in open‐field activity (DeFries et al., 1978, Behavior Genetics, 8: 3–13) and subsequently inbred to use as a genetic model for studying anxiety‐like behaviors (Booher et al., 2021, Genes, Brain and Behavior, 20: e12730). Hippocampal RNA‐sequencing of the High and Low Activity mice identified 3901 differentially expressed protein‐coding genes, with both sex‐dependent and sex‐independent effects. Functional enrichment analysis (PANTHER) highlighted 15 gene ontology terms, which allowed us to create a narrow list of 264 top candidate genes. Of the top candidate genes, 46 encoded four Complexes (I, II, IV and V) and two electron carriers (cytochrome c and ubiquinone) of the mitochondrial oxidative phosphorylation process. The most striking results were in the female high anxiety, Low Activity mice, where 39/46 genes relating to oxidative phosphorylation were upregulated. In addition, comparison of our top candidate genes with two previously curated High and Low Activity gene lists highlight 24 overlapping genes, where Ndufa13, which encodes the supernumerary subunit A13 of complex I, was the only gene to be included in all three lists. Mitochondrial dysfunction has recently been implicated as both a cause and effect of anxiety‐related disorders and thus should be further explored as a possible novel pharmaceutical treatment for anxiety disorders. Overview of differentially expressed genes by strain and sex.
... To the best of our knowledge, all research on oestrous effects on anxiety-like behaviour have been conducted using normally bred adult female rats, with one exception [65] that examined Wistar Kyoto rats, a strain associated with heightened stress sensitivity. Selective breeding for extremes in trait anxiety has produced rodent strains with inborn low or high anxiety-like behaviour [103,104]. Whereas the literature on oestrous effects on anxiety in normally bred rats may offer insights into menstrual-related changes in anxiety in healthy people, future studies testing oestrous effects on anxietylike behaviour in female rodents selectively bred for high anxiety-like behaviour may be a promising animal model for examining the genetic, neurobiological, and endocrinological causes of menstrual-related anxiety fluctuations in clinically anxious women. Additionally, examining oestrous effects on anxiety-like behaviour in both normally bred and high-anxiety rodents may be a useful analogue to examine potential differences in menstrual cycle effects on anxiety between healthy and clinically anxious human populations. ...
Purpose of Review
Anxiety symptoms increase during the peri-menstrual phase of the menstrual cycle in people with anxiety disorders. Whether this reflects a heightened variant of normal menstrual-related changes in psychological states experienced by healthy (i.e. non-anxious) people is unknown. Moreover, menstrual-related change in anxiety symptoms is a poorly understood phenomenon, highlighting a need for pre-clinical models to aid mechanistic discovery. Here, we review recent evidence for menstrual effects on anxiety-like features in healthy humans as a counterpart to recent reviews that have focused on clinically anxious populations. We appraise the utility of rodent models to identify mechanisms of menstrual effects on anxiety and offer suggestions to harmonise methodological practices across species to advance knowledge in this field.
Recent Findings
Consistent with reports in clinical populations, some evidence indicates anxiety symptoms increase during the peri-menstrual period in healthy people, although null results have been reported, and these effects are heterogeneous across studies and individuals. Studies in rats show robust increases in anxiety during analogous phases of the oestrous cycle.
Summary
Studies in female rats are useful to identify the evolutionarily conserved biological mechanisms of menstrual-related changes in anxiety. Future experimental approaches in rats should model the heterogeneity observed in human studies to increase alignment across species and advance understanding of the individual factors that increase the propensity to experience menstrual-related changes in anxiety.
