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Huntington’s disease (HD) is characterised by motor symptoms which are often preceded by cognitive and behavioural changes, that can significantly contribute to disease burden for people living with HD. Numerous knock-in mouse models of HD are currently available for scientific research. However, before their use, they must be behaviourally characterised to determine their suitability in recapitulating the symptoms of the human condition. Thus, we sought to longitudinally characterise the nature, severity and time course of cognitive and behavioural changes observed in HdhQ111 heterozygous knock-in mice.To determine changes in cognition and behaviour an extensive battery of operant tests including: fixed ratio, progressive ratio, the five choice serial reaction time task and the serial implicit learning task, were applied longitudinally to HdhQ111 and wild type mice. The operant test battery was conducted at 6, 12 and 18 months of age. Significant deficits were observed in HdhQ111 animals in comparison to wild type animals in all operant tests indicating altered cognition (attentional and executive function) and motivation. However, the cognitive and behavioural deficits observed were not shown to be progressive over time in the longitudinal testing paradigm that was utilised. The results therefore demonstrate that the HdhQ111 mouse model of HD reflects some features of the cognitive and behavioural changes shown in the human condition of HD. Although, the cognitive and behavioural deficits demonstrated were not shown to be progressive over time. [ABSTRACT FROM AUTHOR]

The characterization of mouse models of human disease is essential for understanding the underlying pathophysiology and developing new therapeutics. Many diseases are often associated with more than one model, and so there is a need to determine which model most closely represents the disease state or is most suited to the therapeutic approach under investigation. In the case of neurological disease, motor tests provide a good read-out of neurological function. This overview of available motor tasks aims to aid researchers in making the correct choice of test when attempting to tease out a transgenic phenotype or when assessing the recovery of motor function following therapeutic intervention. [ABSTRACT FROM AUTHOR]

Abstract: A range of transgenic and knock-in mouse models of Huntington''s disease have been created since identification in 1993 of the disease mutation in the HD gene. Knock-in models that express the full-length mutant protein tend to exhibit less severe behavioural deficits than transgenic models and so require more sensitive tasks in order to reveal impairments. To achieve this, we therefore used a Serial Implicit Learning Task (SILT), which measures serial reaction times to visual stimuli, requiring detection and responding in both predictable and unpredictable locations in the 9-hole operant chamber. We have previously reported that knock-in HdhQ92/Q92 mice exhibit a modest impairment in learning the SILT tasks at 4 months of age, prior to the formation of overt neuronal nuclear inclusions. In the present study we have explored the time course of the development of impairments from 5 to 14 months of age. The deficit previously found in accuracy and reaction time was present at all ages examined in these HdhQ92/Q92 mice; the deficit was not progressive, and did not correlate with the evolution of neuronal nuclear inclusions. [Copyright &y& Elsevier]

Abstract: Within a broader programme developing murine models of Huntington''s disease (HD), we have sought to develop a test of implicit learning for the mouse. Mice were trained in a novel serial visual discrimination task in the ‘9-hole box’ operant test apparatus, followed by retesting after either bilateral quinolinic acid striatal lesions or sham lesions. In the task, each trial involves two sequential responses: an initial light stimulus is presented randomly in one of five holes, to which a nose-poke response results in the first light being extinguished and a second light is illuminated in a different hole. Response to the second light results in food reward, followed by a brief interval before the next trial. When the first light was in one of three of the five holes, the location of the second light was unpredictable in any of the remaining four holes; by contrast, if the first light occurred in one of the other two of the five holes, then the location of the second light was entirely predictable, being the hole two steps to the left or to the right, respectively. Reaction times and accuracy of responding were recorded to both stimuli. The mice learned the task with a degree of accuracy, and they demonstrated clear implicit learning, as measured by increased accuracy and reduced latency to respond to the presentation of the predictable stimulus. Striatal lesions disrupted performance, reducing accuracy for both the first and second stimuli and increasing response latencies for the second stimuli. The decrease in accuracy by the lesioned animals was accompanied by increases in perseverative nose-poking and inappropriate magazine entries throughout the trials, but the lesioned mice still showed a similar benefit (albeit, against a lower baseline of performance) from the implicit knowledge provided on predictable trials. The data validates the task as a sensitive probe for determining implicit learning deficits in the mouse, and suggests that the consequences of striatal lesions, while disrupting performance of skilled stimulus-response habits, are not selective to the process underlying implicit learning. [Copyright &y& Elsevier]

Rationale. To determine the suitability of the nine-hole box to characterise mouse performance on a free operant task and a discrete trials task, and to validate the tests by probing whether d-amphetamine and scopolamine modify performance of the task as predicted. Objectives. To demonstrate the functionality and efficiency of the mouse nine-hole box for the evaluation of performance under fixed- (FR) and progressive-ratio (PR) operant schedules, as well as under a three-choice visual discrimination task and subsequent reversals of the task. In addition, sensitivity of the apparatus was assessed using pharmacological challenges. Methods. C57BL/6J were tested on CRF, FR5, FR10, FR20, and a modified PR3 schedule. Behavioural response to d-amphetamine sulphate (0.1, 0.3, and 2.0 mg/kg for FR and 0.1, 0.3, and 1.0 mg/kg for PR) was assessed. In a separate group of mice trained on a three-choice visual discrimination task, the task was reversed (light+, dark+, light+, dark+) 3 times to determine acquisition and reversal of the visual discrimination rule. Scopolamine hydrobromide was examined in this paradigm with the reversal task, and was used to determine learning acquisition and rule reversal learning. Results. Mice rapidly acquired the FR and PR schedules, as well as both three-choice visual discrimination procedures in the nine-hole box. d-Amphetamine significantly reduced performance on the FR5 and FR10 schedules as shown by the reduction in the number of rewarded responses and the increases in various latency measurements. As expected, d-amphetamine induced an increase in the break point and eliminated the pauses that occurred on high ratio schedules under the PR3 paradigm. Pretreatment of scopolamine decreased accuracy in the three-choice visual discrimination task. Conclusions. The nine-hole box is an effective tool to assess operant behaviours in mice following pharmacological manipulation validating the utility of this apparatus for the behavioural evaluation of drug-induced and transgenic models of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]