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Huntington′s Disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor disturbance, cognitive decline and psychiatric manifestations. The disease typically starts in midlife and symptoms progress over the course of 15–20 years until death. The mutation responsible for HD is an unstable expansion of CAG repeats in the huntingtin gene. Numerous genetic mouse models have been generated and PsychoGenics has phenotypically characterized extensively both transgenic and knock-in models of the disease (Menalled et al., 2010). Currently, PsychoGenics houses the R6/2 and Q175 mouse models. The R6/2 transgenic mouse model was the first developed (Mangiarini et al., 1996) is widely used to understand the pathogenesis of the disease as well as for the evaluation of new therapies. These mice carrying around 120 CAG repeats present severe weight loss, progressive motor, cognitive and psychiatric deficits, and a reduced life expectancy (18-20 weeks). The Q175 Knock-in model derived from a spontaneous expansion from Q140 Knock-in colony, display also a slower progressive motor and cognitive phenotype than the R6/2 model. To view phenotypic data from any HD mouse lines characterized at PsychoGenics, click on any of the experimental tests below.

Accelerating the identification of treatments for HD:

In collaboration with CHDI Foundation and The Jackson Laboratories, PsychoGenics has developed a field guide for researchers using mouse models of Huntington’s disease. The guide describes established and emerging mouse models of HD presenting the differences between models recommendations for colony management as well as preclinical experimental design with the aim of obtaining robust and reproducible results.

Field Guide

R6/2 HD mutant mice

BAC HD mutant mice

R6/2 Arousability

State of arousal, operationally defined in this assay as reactivity to removal of the top of the home cage, is reduced in R6/2 compared to Wild Type (WT) mice. This measure has been suggested as a behavioral model of the apathy characteristic of Huntington’s disease.

Arousability

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R6/2 Body Weight

Body weights are markedly reduced in R6/2 mice, with the onset of reduced growth becoming apparent early in life.

Body Weight

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R6/2 Survival

Whereas the life expectancy of a normal mouse is approximately 2 years, R6/2 mice with 120 CAG repeats exhibit a significantly reduced median survival of 15-17 weeks.

Survival

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R6/2 Grip Strength

Grip strength is used to assess muscular strength in limb muscles. The animal is lowered toward the platform and gently pulled backwards with consistent force by the experimenter until it releases its grip. The grip force is recorded on the strain gauge.

Grip Strength

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R6/2 Open Field

The open field test (OF) is used to assess motor activity. The enclosure is configured to split the open field into a center and periphery zone. Animals that have higher levels of anxiety or lower levels of activity tend to stay in the corners of the OF enclosures. Mice that have high levels of activity and low levels of anxiety tend to spend more time in the center of the enclosure.

Open Field

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R6/2 Rotarod

Motor coordination and exercise capacity are assessed by rotarod. Tests are performed on separate days, with multiple trials per day. Mice are placed on the rotarod and the speed is gradually and uniformly increased over a maximum period of time. The time that each mouse remains on the rotating rod before falling is recorded.

Rotarod

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R6/2 Rearing and Climbing

Rearing-climbing behavior is used to assess motor movement and coordination. The mouse is placed on a flat surface and a closed-top wire mesh cylinder 15 cm X 20 cm tall is placed over the mouse. The animal's behavior is videotaped and the proportion of mice that climb and the latency to climb is measured over a 5 min period.

Rear and Climbing

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R6/2 Contextual Fear Conditioning

The formation of contextual memories is dependent upon the integrity of medial temporal lobe structures including the hippocampus and amygdala. In this assay mice are trained to remember that a particular salient context (conditioned stimulus; CS) is associated with an aversive event, in this case a mild foot shock (the unconditioned stimulus, US). Animals that show good learning freeze upon re-presentation of the context (Contextual Fear Conditioning). For some lines, we also quantify freezing to a tone stimulus paired with a foot shock US (Cued Fear Conditioning).

Contextual Fear Conditioning

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R6/2 Procedural T-Maze Test

Procedural T-maze testing consists of animals in learning an initial left-right procedural discrimination for 6 consecutive days. Animals will be considered to have acquired the task after reaching the acquisition criteria. In this paradigms, R6/2 mice show a cognitive deficit by 9 weeks of age.

Procedural T_Maze Test

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R6/2 Slice Electrophysiology

R6_2 slice electrophysiology R6_2 slice electrophysiology R6_2 slice electrophysiology

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Q175 Body Weight

Q175 Body Weight

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Q175 Survival

Q175 Survival

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Q175 Open Field

Q175 Open Field

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Q175 Rotarod

Q175 Rotarod

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Q175 Motivation

Apathy, which can be defined as a lack of motivation characterized by diminished goal-oriented behavior, is a known symptom of Huntington’s disease and other neurodegenerative disorders. A typical and well controlled assay to probe this domain in rodents in the progressive ratio task, a procedure where food-restricted animals are required to expend progressively increasing effort to obtain successive food reinforcements.

Q175 Progressive Ratio Task

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Q175 Slice Electrophysiology

Q175 slice electrophysiology Q175 slice electrophysiology Q175 slice electrophysiology

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Q175 in vivo Electrophysiology

Q175 in vivo Electrophysiology Q175 in vivo Electrophysiology

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Q175 in vivo Electrophysiology

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Q175 in vivo Electrophysiology

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BAC HD Circadian function

Neurodegenerative diseases are marked by psychiatric and motor problems are often accompanied by deficits in sleep and circadian function. As expected, deficits in sleep-wake patterns have profound consequences in many physiological functions. In Huntington’s Disease patients (HD), for examples, abnormal sleep patterns correlate with symptom severity, specifically in depression and cognitive dysfunction, and in caudate atrophy. We studied the behavior of the BAC HD model using an 24/7 automated home-cage system and custom-built computer vision assessment of behavior, PhenoCube®. Using this system we could, in just 6 days, measure a significant lengthening of the circadian period in the mutants. The results reinforce previous findings in the R6/2 mouse and in a transgenic rat model of HD [2,3], indicating that circadian dysfunction is a fundamental feature of HD. These results also provide the validation of PhenoCube® as a system for the fast assessment of circadian function.

Circadian Function Circadian Function

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BAC HD Motivation

Apathy, which can be defined as a lack of motivation characterized by diminished goal-oriented behavior, is a known symptom of Huntington’s disease and other neurodegenerative disorders. A typical and well controlled assay to probe this domain in rodents in the progressive ratio task, a procedure where food-restricted animals are required to expend progressively increasing effort to obtain successive food reinforcements.

Motivation

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