Repair of the CNS using endogenous and transplanted neural stem cells.

Restoration of the damaged central nervous system is a vast challenge. However, there is a great need for research into this topic, due to the prevalence of central nervous system disorders and the devastating impact they have on people's lives. A number of strategies are being examined to achieve this goal, including cell replacement therapy, enhancement of endogenous plasticity and the recruitment of endogenous neurogenesis. The current chapter reviews this topic within the context of Parkinson's disease, Huntington's disease and stroke. For each disease exogenous cell therapies are discussed including primary (foetal) cell transplants, neural stem cells, induced pluripotent stem cells and marrow stromal cells. This chapter highlights the different mechanistic approaches of cell replacement therapy versus cells that deliver neurotropic factors, or enhance the endogenous production of these factors. Evidence of exogenously transplanted cells functionally integrating into the host brain, replacing cells, and having a behavioural benefit are discussed, along with the ability of some cell sources to stimulate endogenous neuroprotective and restorative events. Alongside exogenous cell therapy, the role of endogenous neurogenesis in each of the three diseases is outlined and methods to enhance this phenomenon are discussed.

Five choice serial reaction time performance in the HdhQ92 mouse model of Huntington's disease.

Huntington's disease is an autosomal dominant genetic disorder, with motor, cognitive and psychiatric symptoms. To date there is no cure. In order to understand better this disease and to develop novel treatments, many genetically modified animal models of Huntington's disease have been created. However, to utilize these models fully, appropriate functional assays need to be developed for behavioural assessments of the mice. Various facets of attention have been reported to be affected in Huntington's disease patients, and the Hdh(Q92/Q92) mice have been shown to have deficits on operant tasks which have attentional components. In the present study, the Hdh(Q92/Q92) mouse model is assessed on a well established test of attentional function, the operant 5-choice serial reaction time task (5-CSRT), in which the mice must respond with a nose poke to light stimuli presented randomly across a 5 hole light array to receive a reward. In the present paper, the Hdh(Q92/Q92) mice exhibited deficits on the 5-CSRT when pseudorandomly presented with stimuli of different durations. However, alterations in the pacing of the task, therefore requiring an increase in sustained attention, did not affect the Hdh(Q92/Q92) mice more than their wildtype littermates. This study indicates that the Hdh(Q92/Q92) mice may have deficits in aspects of attentional function, in particular disruption in the ability to maintain attention in the visuospatial domain, suggesting that this knock-in mouse model of Huntington's disease may be a relevant model of the disease for the testing of novel therapeutic interventions.

Early onset deficits on the delayed alternation task in the Hdh(Q92) knock-in mouse model of Huntington's disease.

A number of genetic mouse models of Huntington's disease have been created, in order to examine the pathogenesis of Huntington's disease and to test potential therapeutics. In the present study we demonstrate that the full-length knock-in homozygote Hdh(Q92) mice exhibit impairments at 5 months of age on the delayed alternation task, conducted in 9-hole operant chambers. This test is sensitive to cortico-striatal dysfunction and demonstrates again that although Hdh(Q92) mice do not display an overt motor phenotype, they do exhibit clear impairments that can be related to deficits seen in HD patients. This indicates that if appropriately sensitive tasks are used, the more subtle and specific Hdh(Q92) knock-in model could be of use for the examination of pathogenic mechanisms in Huntington's disease and to test potential therapeutics.

Operant-based instrumental learning for analysis of genetically modified models of Huntington's disease.

Huntington's disease is the result of an expanded CAG repeat in the gene that codes for the protein huntingtin and results in a progressive sequelae of motor, cognitive and psychiatric symptoms. The development of genetically modified rodent models of Huntington's disease has led to the need for sensitive behavioural phenotyping. Operant tests for rodents have been developed that can determine the functional deficits in these genetically modified models, from motor, cognitive and emotional domains. The current review discusses tests that employ operant equipment, an automated and highly flexible method for testing rodents. Different operant paradigms are examined in relation to their relevance to Huntington's disease symptomology, as well as summarising research to date on genetic models with these tests.

Challenges facing quantification of rat locomotion along beams of varying widths.

Optoelectronic motion capture systems have been widely used to investigate temporal gait parameters in humans and animals in order to understand function and behavioural attributes of different pathologies, e.g. Parkinson's disease (PD). The aim of the present paper was to investigate the practicality of utilising this system to investigate the effects of a unilateral 6-hydroxydopamine (6-OHDA) lesion on rat locomotion while walking on beams of varying widths (graduated, narrow, and wide). Temporal gait parameters of ten male Lister Hooded rats (five controls and five hemiparkinsonian) were observed using passive markers placed in locations that were representative of their four limbs and their body axis. The results demonstrate that marker-based motion capture can provide an effective and simple approach to quantifying temporal gait parameters for rat models of PD. They also reveal how the width of the path affects the locomotion in both experimental cohorts. Such measurements can be compared with human motion analysis to explore correlations between the animal model and human behaviour, which is an important step for translational medicine.

Rule learning, visuospatial function and motor performance in the Hdh(Q92) knock-in mouse model of Huntington's disease.

Among a range of genetic mouse models of Huntington's disease, knock-in models that express full-length mutant huntingtin tend to have a slower developing and less severe behavioural phenotype than transgenic models carrying truncated variations of the human gene; as a result, these more subtle full-length knock-in models have been relatively neglected for behavioural and therapeutic studies. In the current study, we show that full-length knock-in Hdh(Q92) mice exhibit marked impairments at a relatively young age in delayed alternation, a cognitive test conducted in 9-hole operant chambers classically associated with prefrontal and corticostriatal function. Additional tests of motivation, visuomotor and rotarod performance were undertaken to determine the frontal-like specificity of the impairment; aspects of sensorimotor and motivational as well as cognitive performance were deficient in Hdh(Q92/Q92) mice in comparison with their wildtype littermates by 27 months of age. The present results demonstrate that Hdh(Q92/Q92) mice do exhibit clear impairments on a range of sensory, motor, motivational and cognitive tests, provided appropriate sensitive tasks are used.

Selective extra-dimensional set shifting deficit in a knock-in mouse model of Huntington's disease.

People with early-stage Huntington's disease have been found to have a specific deficit in performing an extra-dimensional shift. To date no evidence of this deficit has been identified in transgenic or knock-in rodent models of the disease. The aim of the present paper then, was to test whether homozygous knock-in mice derived from the Hdh(CAG(150)) mouse line were impaired in any of five 2-choice discrimination tasks (simple, compound, compound reversal, intra-dimensional shift and extra-dimensional shift), and whether these mice were impaired at recalling these tasks on the following day. On the extra-dimensional shift task the Hdh(CAG(150)) homozygous mice required a greater number of trials to reach criteria than mice and the percentage of correct choices within the trials was also significantly reduced compared with the animals. For the recall tasks, a deficit for recalling the compound reversal test was found in the Hdh(CAG(150)) homozygous mice for both number of trials required to reach criteria and percentage of correct choices within the trials. Recall for the intra-dimensional shift task was also impaired in these animals when measured by the percentage of correct choices. Our results demonstrate a pronounced deficit in the Hdh(CAG(150)) mice not only on extra-dimensional shift performance in agreement with human studies, but also on recall tasks for both the compound reversal and the intra-dimensional shift tasks.