Assessment of genetic susceptibility to ethanol intoxication in mice

Abstract

Increased use of gene manipulation in mice (e.g., targeted or random mutagenesis) has been accompanied by increased reliance on a very few rapid and simple behavioral assays, each of which aspires to model a human behavioral domain. Yet, each assay comprises multiple traits, influenced by multiple genetic factors. Motor incoordination (ataxia), a common characteristic of many neurological disorders, may reflect disordered balance, muscle strength, proprioception, and͞or patterned gait. Impaired motor performance can confound interpretation of behavioral assays of learning and memory, exploration, motivation, and sensory competence. The rotarod is one of the most commonly used tests to measure coordination in mice. We show here that exactly how the rotarod test is performed can markedly alter the apparent patterns of genetic influence both in undrugged performance and sensitivity to ethanol intoxication. However, when tested with well chosen parameters, the accelerating rotarod test showed very high inter-and intralaboratory reliability. Depending on test conditions, ethanol can either disrupt or enhance performance in some strains. Genetic contribution to performance on the accelerating versus the fixed-speed rotarod assay can be completely dissociated under some test conditions, and multiple test parameters are needed to assess the range of genetic influence adequately.T he loss of motor coordination (ataxia) is a common characteristic of many neurological disorders and a frequent endpoint for studies of drug intoxication. Therefore, behavioral assays that model ataxia are of great importance to researchers who are interested in learning more about the mechanisms of drug action and disease. One of the most commonly used tests of motor incoordination is the rotarod (1-4), which has two variants: the accelerating rotarod (ARR) and the fixed-speed rotarod (FSRR). Studies of inbred strains (5-8), selected lines (9), and transgenic animals (10-12) have shown that rotarod performance is highly influenced by genetic background in mice. Genetically distinct mice often differ in their undrugged ability to perform, and differ in their sensitivities to ethanol and other drugs on the task.Although the rotarod is widely used in biomedical research, there is little consensus on the ideal parameters and test schedules to produce optimal results. We have recently completed studies in genetically heterogeneous mice examining the influence of different rod diameters, rotation rate, and training regimens on rotarod performance, as well as their effects on sensitivity to ethanol intoxication. We obtained some expected results (e.g., training on the ARR improved performance, and performance was influenced by acceleration rate). More surprisingly, we found that higher acceleration rates suppressed sensitivity to ethanol intoxication. We also found that rod diameter did not markedly affect performance, provided that the diameter was large enough to prevent passive rotation on the rod (13).Many researchers appear to design behavioral ...

Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissure and absent corpus callosum

“…Nevertheless, strain BTBR T/ + tf/tf is among the best performers on the accelerating rotarod test of motor coordination [14,15]. Just as the effects of a targeted mutation that impair CC development depend on the genetic background [11], the behavioral consequences of an anatomical CC defect may also depend on the genetic background.…”

“…The 40 strains are divided into priority groups A, B, C, and D with ten strains each [20], chosen to represent a wide diversity of mouse genotypes. At the outset of the MPP in 1999, the highest priority group A included the little known strain BTBR T / + tf/tf, but that strain was later moved by MPP staff to the lowest priority group D. Our work with behavioral tests in two laboratories began in 2000 with the original group A, and we found some interesting behavioral differences in the BTBR mice, especially their superior performance on the accelerating rotarod [14,15]. Consequently, when we expanded our study in 2002 to include the 20 strains in priority groups A and B, we included BTBR from group D and assessed brain size and commissure anatomy of 21 inbred strains.…”

“…On Monday there was a 5-min trial in the open field, followed by 5 min on an elevated plus maze on Tuesday. On Wednesday there were ten acquisition trials on the accelerating rotarod [14,15], followed by rotarod trials before and after a saline injection on Thursday and before and after an ethanol injection (2 mg/kg) on Friday. The next week there was 1 day of pretraining and then 4 days of training on a hidden platform water escape task [20].…”

The parallel rod floor test: a measure of ataxia in mice

“…All the above mentioned tasks are sensitive to genetic differences (e.g., among inbred mouse strains or between mutants and wild types) 3,4,[12][13][14] ; however, when the genotypic differences in performance on these tasks were compared across eight inbred strains of mice, strain sensitivities showed only modest correlations among tasks 15 . Thus, the tasks were not tapping a single underlying construct, and 'ataxia' is not a simple, monolithic trait insofar as its genetic contributions are concerned.…”

“…This is in contrast to several other measures of ataxia, such as the rotarod, where the parameters of the task (e.g., rate of acceleration of rotation) have been shown to have large effects on the pattern of strain sensitivity. For example, comparing inbred strain data from an accelerating rod with those from the same apparatus rotating at a fixed speed yielded unrelated patterns of strain differences 14 .…”