Early Detection of Apathetic Phenotypes in Huntington’s Disease Knock-in Mice Using Open Source Tools

Minnig, Shawn; Bragg, Robert M.; Tiwana, Hardeep S.; Solem, Wes T.; Hovander, William S.; Vik, Eva-Mari S.; Hamilton, Madeline; Legg, Samuel R. W.; Shuttleworth, Dominic D.; Coffey, Sydney R.; Cantle, Jeffrey P.; Carroll, Jeffrey B.

doi:10.1038/s41598-018-20607-7

Cited by 7 publications

(7 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The discrepancies between breakpoint data in this study and published reports likely stem from a differential setting (touch screen chambers vs. lever-equipped operant boxes or operant buckets) and steeper, PR8, reinforcement schedule than those employed in other studies in which breakpoints were achieved (Covey et al, 2016 ; Yhnell et al, 2016a ; Minnig et al, 2018 ). Also, there was a subtle genetic difference between Q175Δ neo mice in our experiments and zQ175 mice used in published studies.…”

Section: Discussioncontrasting

confidence: 90%

“…Lower response (target touch) rate in Q175Δ neo mice was noted also in our experiments (Figures 8D , 9E ), however, the breakpoints, which correlate with the number of earned rewards, were similar in WT and mutant animals (Figure 9A ). Lower breakpoint values were also described in HdhQ111 mice (Yhnell et al, 2016a ; Minnig et al, 2018 ).…”

Section: Discussionmentioning

confidence: 65%

See 1 more Smart Citation

Impaired Performance of the Q175 Mouse Model of Huntington’s Disease in the Touch Screen Paired Associates Learning Task

Piiponniemi¹,

Parkkari²,

Heikkinen³

et al. 2018

Front. Behav. Neurosci.

View full text Add to dashboard Cite

Cognitive disturbances often predate characteristic motor dysfunction in individuals with Huntington’s disease (HD) and place an increasing burden on the HD patients and caregivers with the progression of the disorder. Therefore, application of maximally translational cognitive tests to animal models of HD is imperative for the development of treatments that could alleviate cognitive decline in human patients. Here, we examined the performance of the Q175 mouse knock-in model of HD in the touch screen version of the paired associates learning (PAL) task. We found that 10–11-month-old heterozygous Q175 mice had severely attenuated learning curve in the PAL task, which was conceptually similar to previously documented impaired performance of individuals with HD in the PAL task of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Besides high rate of errors in PAL task, Q175 mice exhibited considerably lower responding rate than age-matched wild-type (WT) animals. Our examination of effortful operant responding during fixed ratio (FR) and progressive ratio (PR) reinforcement schedules in a separate cohort of similar age confirmed slower and unselective performance of mutant animals, as observed during PAL task, but suggested that motivation to work for nutritional reward in the touch screen setting was similar in Q175 and WT mice. We also demonstrated that pronounced sensorimotor disturbances in Q175 mice can be detected at early touch screen testing stages, (e.g., during “Punish Incorrect” phase of operant pretraining), so we propose that shorter test routines may be utilised for more expedient studies of treatments aimed at the rescue of HD-related phenotype.

show abstract

Section: Discussioncontrasting

confidence: 90%

Section: Discussionmentioning

confidence: 65%

Impaired Performance of the Q175 Mouse Model of Huntington’s Disease in the Touch Screen Paired Associates Learning Task

Piiponniemi¹,

Parkkari²,

Heikkinen³

et al. 2018

Front. Behav. Neurosci.

View full text Add to dashboard Cite

show abstract

“…This may have exacerbated motor deficits as well as worsening motivation deficits and apathy-like behavior, which have been shown in HD mice. 32,33 In sum, our behavioral results reveal progressive deficits in paw kinematics and motor refinement on the rotarod in YAC128 mice.…”

Section: Rotarod Deficits and Paw Kinematics In Premanifest And Manif...mentioning

confidence: 58%

Early Changes in Striatal Activity and Motor Kinematics in a Huntington's Disease Mouse Model

et al. 2022

View full text Add to dashboard Cite

A BS TRACT: Background: Huntington's disease is a progressive neurodegenerative disorder with no diseasemodifying treatments. Patients experience motor, cognitive, and psychiatric disturbances, and the dorsal striatum is the main target of neurodegeneration. Mouse models of Huntington's disease show altered striatal synaptic signaling in vitro, but how these changes relate to behavioral deficits in vivo is unclear. Objectives: We aimed to investigate how striatal activity correlates with behavior in vivo during motor learning and spontaneous behavior in a Huntington's disease mouse model at two disease stages. Methods: We used fiber photometry to record jGCaMP7f fluorescence, a read-out of neuronal activity, in the dorsal striatum of YAC128 (yeast artificial chromosome-128CAG) mice during accelerating rotarod and open-field behavior. Results: Mice showed increased striatal activity on the rotarod, which diminished by late stages of learning, leading to an inverse correlation between latency to fall and striatal activity. The 2-to 3-month-old YAC128 mice did not show a deficit in latency to fall, but displayed significant differences in paw kinematics, including increased paw slip frequency and variability in paw height. These mice exhibited a weaker correlation between latency to fall and striatal activity and aberrant striatal activity during paw slips. At 6 to 7 months, the YAC128 mice showed significantly reduced latency to fall, impaired paw kinematics, and increased striatal activity while on the rotarod. In the open field, the YAC128 mice showed elevated neuronal activity at rest. Conclusions: We uncovered impaired motor coordination at a stage thought to be premotor manifest in YAC128 mice and aberrant striatal activity during the accelerating rotarod and open-field exploration.

show abstract

“…Alternatively, impaired learning of the task may be related to an inability to use rewards as a learning signal to effectively modulate the kinematic parameters of future movements. Although HD mouse models have previously been reported to have motivational deficits on operant progressive ratio tasks (Covey et al, 2016;Minnig et al, 2018), Q175-FDN mice actually performed a greater number of trials compared with WT mice, suggesting that altered motivation to perform the task was not a major contributor to the observed impairments.…”

Section: Discussionmentioning

confidence: 90%

Impaired Refinement of Kinematic Variability in Huntington Disease Mice on an Automated Home Cage Forelimb Motor Task

2021

View full text Add to dashboard Cite

The effective development of novel therapies in mouse models of neurologic disorders relies on behavioral assessments that provide accurate read-outs of neuronal dysfunction and/or degeneration. We designed an automated behavioral testing system (PiPaw), which integrates an operant lever-pulling task directly into the mouse home cage. This task is accessible to grouphoused mice 24 h per day, enabling high-throughput longitudinal analysis of forelimb motor learning. Moreover, this design eliminates the need for exposure to novel environments and minimizes experimenter interaction, significantly reducing two of the largest stressors associated with animal behavior. Male mice improved their performance of this task over 1 week of testing by reducing intertrial variability of reward-related kinematic parameters (pull amplitude or peak velocity). In addition, mice displayed short-term improvements in reward rate, and a concomitant decrease in movement variability, over the course of brief bouts of task engagement. We used this system to assess motor learning in mouse models of the inherited neurodegenerative disorder, Huntington disease (HD). Despite having no baseline differences in task performance, male Q175-FDN HD mice were unable to modulate the variability of their movements to increase reward on either short or long timescales.Task training was associated with a decrease in the amplitude of spontaneous excitatory activity recorded from striatal medium spiny neurons in the hemisphere contralateral to the trained forelimb in WT mice; however, no such changes were observed in Q175-FDN mice. This behavioral screening platform should prove useful for preclinical drug trials toward improved treatments in HD and other neurologic disorders.

show abstract

Early Detection of Apathetic Phenotypes in Huntington’s Disease Knock-in Mice Using Open Source Tools

Cited by 7 publications

References 46 publications

Impaired Performance of the Q175 Mouse Model of Huntington’s Disease in the Touch Screen Paired Associates Learning Task

Impaired Performance of the Q175 Mouse Model of Huntington’s Disease in the Touch Screen Paired Associates Learning Task

Early Changes in Striatal Activity and Motor Kinematics in a Huntington's Disease Mouse Model

Impaired Refinement of Kinematic Variability in Huntington Disease Mice on an Automated Home Cage Forelimb Motor Task

Contact Info

Product

Resources

About