Adaptation of the Arizona Cognitive Task Battery for use with the Ts65Dn mouse model (Mus musculus) of Down syndrome

Abstract

We propose and validate a clear strategy to efficiently and comprehensively characterize neurobehavioral deficits in the Ts65Dn mouse model of Down syndrome. This novel approach uses neurocognitive theory to design and select behavioral tasks that test specific hypotheses concerning the results of Down syndrome. In this article, we model the Arizona Cognitive Task Battery, used to study human populations with Down syndrome, in Ts65Dn mice. We observed specific deficits for spatial memory, impaired long-term memory for visual objects, acquisition and reversal of motor responses, reduced motor dexterity, and impaired adaptive function as measured by nesting and anxiety tasks. The Ts65Dn mice showed intact temporal ordering, novelty detection, and visual object recognition with short delays. These results phenocopy the performance of participants with Down syndrome on the Arizona Cognitive Task Battery. This approach extends the utility of mouse models of Down syndrome by integrating the expertise of clinical neurology and cognitive neuroscience into the mouse behavioral laboratory. Further, by directly emphasizing the reciprocal translation of research between human disease states and the associated mouse models, we demonstrate that it is possible for both groups to mutually inform each other's research to more efficiently generate hypotheses and elucidate treatment strategies. (PsycINFO Database Record

Figure 1

Dry land water maze performance on a cheeseboard for Ts65Dn and 2N wildtype control mice. Ts65Dn mice showed impaired spatial navigation abilities during the 4 days of acquisition, even when adjusted for initial performance. Ts65Dn mice also show spatial memory deficits during the probe trial relative to 2N wildtype control mice, reflected in reduced time in the quadrant containing the reward location and greater average distance from the previously rewarded location compared to 2N control mice. a. Raw latency (s) to reach goal location each day b. Percentage of Day 1 latency to reach goal location c. Raw distance (cm) to reach goal location d. Percentage of Day 1 distance to reach goal location e. Percentage of time during probe in same quadrant as goal location f. Average distance from goal location during probe trial

Figure 2

Spatial and Temporal Attribute task battery. The data suggest Ts65Dn mice show deficits relative to 2N wildtype control mice for location recognition and metric/coordinate processing, but no deficits for topological/categorical processing. The Ts65Dn mice do not show deficits for temporal ordering for visual objects compared to 2N wildtype control mice. a. Performance on a Metric/Coordinate Processing test b. Performance on a Topological/Categorical Processing test c. Performance on a Location Recognition test d.Performance on a Temporal Ordering for Visual Objects test e. Performance on a Novelty Detection for Visual Objects test

Figure 3

Sensory/Perceptual Attribute task battery. Overall, Ts65Dn mice do not show impaired sensory/perceptual function relative to 2N wildtype mice. Ts65Dn mice also do not show deficits for object recognition at a 1 hour delay, but do show deficits for object recognition at 24 hour delays. a. Detection of Visual Object Feature Ambiguity b. Detection of Visual Object Feature Novelty c. Performance on an Object Recognition at 1 Hour Delay test d. Performance on an Object Recognition at 24 Hour Delay test

Figure 4

Executive Function/Rule Based Memory Task Battery. Ts65Dn mice show fewer alternations on a spontaneous alternation task relative to 2N control mice. Ts65Dn mice show mild deficits for acquisition and reversal of a rule based response on a plus maze. During reversal training, Ts65Dn mice learn to apply the new rule on later trials than control mice, reflected by an increased number of perseverative, but not regressive, errors. a. Performance on a Spontaneous Alternation test b. Acquisition of a Rule Response on a plus maze c. Acquisition of a Rule Reversal on a plus maze d. Changepoint analysis of Rule Reversal acquisition e. Perseverative Errors during trials 1–20 f. Regressive Errors during trials 21–40

Figure 5

Motor Function Task Battery. Ts65Dn mice showed reduced motor dexterity during a Capellini Handling task reflected as an increase in the number of abnormal behaviors and increased latency to consume the capellini as well a greater number of foot slips during a Parallel Rung Walking task, even when adjusted for total number of steps. a. Latency (s) to consume capellini b. Total number of abnormal behaviors c. Number of times paws came together and touched d. Number of times paw lost contact e. Total number of times mouth was used to move capellini f. Total number of foot slips on a Parallel Rung Walking test g.Total number of foot slips when adjusted for total number of steps

Figure 6

Adaptive Function/Quality of Life Task Battery. Ts65Dn mice take longer to make a nest out of preferred nesting material and show increased neophobia for both food and environments. a. Latency (s) to initially contact nesting material. b. Latency (s) to begin digging in nesting material c. Total latency (s) to finish nest d. Latency (s) to begin consuming novel food in familiar environment e. Latency (s) to consume familiar food in novel environment. f. Latency (s) to consume novel food in novel environment