A phenotypic characterisation of the HdhQ111 mouse model of Huntington’s disease

The work presented in this thesis focuses on a behavioural and histological characterisation of the HdhQ111 mouse model of Huntington’s disease (HD). Numerous mouse models of HD are currently available; however, before their use, each must be fully understood, validated and characterised, which will allow the most appropriate model to be used in scientific research. Chapter 1 provides a general introduction. Chapter 2 states the materials and methods used in this thesis. The work presented in Chapter 3 encompasses an extensive longitudinal immunohistological characterisation of the HdhQ111/+ mouse model, which includes immunohistochemical stains from animals at 3, 6, 9, 12, 15 and 18 months of age, to understand the development of the underlying neuropathology associated with this mouse model. Chapter 4 builds on the knowledge gained from the previous chapter to explore the longitudinal progression of motor symptoms associated with the HdhQ111/+ mouse model. In Chapter 5 a longitudinal operant battery was conducted to explore cognitive dysfunction in the HdhQ111/+ mouse model. Operant tests of motivation, attention and implicit learning were conducted longitudinally at 6, 12 and 18 months of age. Chapter 6 uses the knowledge gained from Chapter 5 to explore the effects of operant pre-training, at a young age, and the impact that this has on latter operant task performance and the development of the disease phenotype at an older age. To further understand the cognitive deficits observed in the HdhQ111/+ mouse model, Chapter 7 presents the creation, optimisation and utilisation of an operant delayed matching and delayed non-matching to position (DMTP/DNMTP) task, which could be used to test working memory and reversal learning in mouse models of neurological diseases including HD. Chapter 8 includes a general discussion of the work presented in this thesis. The studies presented within this thesis demonstrate the development of a clear neuropathological profile as well as significant motor and cognitive deficits in the HdhQ111 mouse model of Huntington’s disease. We can therefore conclude that the HdhQ111 mouse model is a valid mouse model for investigating the pathogenic mechanisms of Huntington's disease and for testing therapeutic interventions in HD

A longitudinal motor characterisation of the HdhQ111 mouse model of Huntington's Disease

Background: Huntington’s disease (HD) is a rare, incurable neurodegenerative disorder caused by a CAG trinucleotide expansion with the first exon of the huntingtin gene. Numerous knock-in mouse models are currently available for modelling HD. However, before their use in scientific research, these models must be characterised to determine their face and predictive validity as models of the disease and their reliability in recapitulating HD symptoms. Objective: Manifest HD is currently diagnosed upon the onset of motor symptoms, thus we sought to longitudinally characterise the progression and severity of motor signs in the HdhQ111 knock-in mouse model of HD, in heterozygous mice. Methods: An extensive battery of motor tests including: rotarod, inverted lid test, balance beam, spontaneous locomotor activity and gait analysis were applied longitudinally to a cohort of HdhQ111 heterozygous mice in order to progressively assess motor function. Results: A progressive failure to gain body weight was demonstrated from 11 months of age and motor problems in all measures of balance beam performance were shown in HdhQ111 heterozygous animals in comparison to wild type control animals from 9 months of age. A decreased latency to fall from the rotarod was demonstrated in HdhQ111 heterozygous animals in comparison to wild type animals, although this was not progressive with time. No genotype specific differences were demonstrated in any of the other motor tests included in the test battery. Conclusions: The HdhQ111 heterozygous mouse demonstrates a subtle and progressive motor phenotype that begins at 9 months of age. This mouse model represents an early disease stage and would be ideal for testing therapeutic strategies that require elongated lead-in times, such as viral gene therapies or striatal transplantation

Reviving the lecture: Using visually dynamic approaches to teach physiological concepts

The educational benefit of the traditional didactic lecture to learners in Higher Education is hotly debated. Given increasing student numbers, existing technical set ups and many logistical concerns, lectures remain the norm in many Higher Education Institutions (HEIs). In this personal view piece, we discuss the benefits, opportunities, and challenges of incorporating dynamic teaching approaches, including “draw-alongs” and animations into undergraduate lectures, typically with large class sizes, to create more engaging and interactive lectures for learners

Cognitive training modifies disease symptoms in a mouse model of Huntington's disease

Huntington's disease (HD) is an incurable neurodegenerative disorder which causes a triad of motor, cognitive and psychiatric disturbances. Cognitive disruptions are a core feature of the disease, which significantly affect daily activities and quality of life, therefore cognitive training interventions present an exciting therapeutic intervention possibility for HD. We aimed to determine if specific cognitive training, in an operant task of attention, modifies the subsequent behavioural and neuropathological phenotype of the Hdh(Q111) mouse model of HD. Three testing groups comprising both Hdh(Q111) mice and wildtype controls were used. The first group received cognitive training in an operant task of attention at 4 months of age. The second group received cognitive training in a comparable non-attentional operant task at 4 months of age, and the third group were control animals that did not receive cognitive training. All groups were then tested in an operant task of attention at 12 months of age. Relative to naïve untrained mice, both wildtype and Hdh(Q111) mice that received cognitive training in the operant task of attention demonstrated an increased number of trials initiated, greater accuracy, and fewer ‘time out’ errors. A specific improvement in response time performance was observed in Hdh(Q111) mice, relative to naïve untrained Hdh(Q111) mice. Relative to the group that received comparable training in a non-attentional task, both wildtype and Hdh(Q111) mice that received attentional training demonstrated superior accuracy in the task and made fewer ‘time out’ errors. Despite significant behavioural change, in both wildtype and Hdh(Q111) mice that had received cognitive training, no significant changes in neuropathology were observed between any of the testing groups. These results demonstrate that attentional cognitive training implemented at a young age significantly improves attentional performance, at an older age, in both wildtype and Hdh(Q111) mice. Attentional cognitive training also improved motor performance in Hdh(Q111) mice, thus leading to the conclusion that cognitive training can improve disease symptoms in a mouse model of HD

Giant genes! The development of an interactive game to engage audiences in genetics

We describe the design, creation, and preliminary evaluation of a hands-on interactive game, “Giant Genes,” which was developed to explain the concept of genetics and the central dogma of gene expression to audiences at Cardiff University’s Brain Games. The Giant Genes game is a modified version of the traditional game “Jenga.” The game begins with a central tower of wooden blocks which are stacked to create a “deoxyribonucleic acid (DNA) tower”. Players then pick amino acid cards which show the three nucleotides that they need to remove from the tower to create a corresponding amino acid. Taking turns in removing blocks from the tower, the player who has created the most amino acids by the time the tower falls wins. After initial positive reviews, we further piloted the game at events including during school visits and a patient interest day. The Giant Genes game is a simple hands-on interactive activity which has attracted diverse audiences. It acts as a fun, informal way of discussing complex genetic issues with the general public and has received positive feedback in preliminary evaluation. The preliminary data demonstrate proof-of-concept that the game can be used successfully with a range of audiences