Amnesia impairs episodic memory in humans, and can occur following damage to the medial diencephalon. This thesis examines the importance of the anterior thalamic nuclei, a diencephalic structure, for different elements (what, when, where) of episodic memory (or episodic-like memory) in rats. The overall goal was to understand why this region is so critical for normal memory in humans. An initial series of experiments investigated the ability of rats with anterior thalamic lesions to recognise objects and odours with a variety of delays. These experiments found that anterior thalamic lesions spare item recognition (what). This same ability was further explored with the use of the immediate early gene zif268, and the results again indicated that this thalamic nucleus does not have a direct role in recognition. A related series of studies explored the effects of anterior thalamic lesions on temporal order judgments (when) for objects. Two different discrimination procedures were tested, between-block recency and within-block recency. Lesions to the anterior thalamic nuclei selectively impaired performance on within-block recency but spared between-block recency. The ability of rats with anterior thalamic damage to discriminate between two locations (where) in both complex and simple environments was also tested. Anterior thalamic lesions significantly impaired place learning compared with control animals, despite the finding that rats with anterior thalamic lesions could sometimes discriminate between the two locations (i.e., could perform significantly above chance). In addition, the effects of anterior thalamic damage on biconditional learning (what-where conjunction) were examined. The rats were trained on both item-place and item-context associations. Lesions to the anterior thalamic nuclei disrupted acquisition of the former, but not the latter. The results suggest that the contributions of the rodent anterior thalamic nuclei to episodic memory, as part of the extended-hippocampal system, primarily reflect the involvement of these nuclei in allocentric spatial learning.

The thesis investigates reasons for a failure of neutrophils to clear pulmonary bacterial infection in cystic fibrosis (CF). Patients with CF experience bacterial colonization of the lungs associated with progressive lung injury and poor prognosis. Neutrophil responsiveness in vitro was determined in patients with CF at different clinical states, and compared to healthy subjects. Neutrophils from the patients were able to phagocytose and kill Pseudomonas aeruginosa effectively, but the presence of sputum sol reduced intracellular killing. Superoxide generation and elastase release in response to fMLP were shown to be reduced in neutrophils from patients with an exacerbation of respiratory symptoms. This was not observed when the cells were stimulated with PMA, which acts intracellularly, rather than through cell surface receptors. There was no difference in the down-regulation of cell surface L-selectin and up-regulation of CD11b in response to fMLP suggesting no alteration in number or function of the fMLP receptors. There was increased adherence to nylon columns by neutrophils from patients with CF. Infection resulted in a greater proportion of band neutrophils, and this correlated with the reduced superoxide generation and elastase release, although it was not possible to separate the band forms to prove this conclusively. Alterations in circulating lipid and fatty acid composition inpatients could potentially affect neutrophil membrane composition and fluidity and therefore signal processing or release of products. The reason for the observed reduced responsiveness appears to be multifactorial. Band cell number post receptor signalling and/or receptor desensitization may result in the observed reduced responsiveness, which returns towards healthy subject levels after treatment of an exacerbation, is likely to be the result of chronic infection.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which there is no cure. At the neuropathological level, AD is characterized by the presence of large numbers of amyloid-beta containing plaques (Aβ-plaques), and neurofibrillary tangles comprised mostly of hyperphosphorylated aggregated protein tau. Both types of deposit are associated with neuroinflammation, synaptic and neuronal cell loss. Accumulating evidence indicates a role for metabolic dysfunction in the pathogenesis of AD. Type 2 diabetes increases the risk of developing AD and several post-mortem analyses have reported evidence of insulin resistance in Alzheimer brain tissue. Insulin-based therapies have emerged as potential strategies to slow cognitive decline in AD, these include the use of insulin sensitizers, such as rosiglitazone, which mediates its effects on insulin sensitivity via the peroxisome proliferator-activated receptors-gamma (PPAR-γ) receptor. While the results of insulin sensitizers on cognition in animal models of AD have been largely positive, the impact of these compounds on cognitive decline in AD patients has been variable. Animal experiments provide a unique opportunity to examine the specific conditions and mechanisms by which insulin sensitizer’s impact on AD-related pathology. This thesis details experiments conducted in a popular Amyloid Precursor Protein overexpressing transgenic mouse model of amyloid pathology that overproduces human Aβ. The aim of these experiments was to determine if chronic dosing with rosiglitazone ameliorated phenotypic behavioural deficits in transgenic mice, and lowered specific biomarkers associated with Aβ over-production. The results indicate that rosiglitazone largely does not reverse phenotypic behavioural alterations in these mice, nor does it reduce total Aβ levels. From this preclinical data, it is concluded that rosiglitazone is likely not a suitable therapeutic treatment for use in human patients with AD.

The pathophysiology of acute post-stroke hyperglycaemia (PSH) is important as hyperglycaemia affects the majority of stroke patients, and is consistently associated with poorer outcome in terms of survival, disability and markers of brain injury such as infarct expansion. There appears to be an interaction between brain arterial patency and hyperglycaemia that has not been fully characterised. This thesis initially reviews the literature on hyperglycaemia and stroke before focusing on animal models of PSH and clinical trials of insulin treatment for PSH in two systematic reviews with meta-analysis. The thesis then looks at the relationship between glucose profiles and clinical outcome in a historical population receiving IV thrombolysis for acute ischaemic stroke, specifically exploring alternative indices of glycaemic state to compare the optimal predictive index for functional outcome as measured by the modified Rankin scale. The main body of the thesis details a prospective observational clinical study which recruited 108 patients within 6 hours of acute ischaemic stroke. These patients had careful monitoring of blood glucose levels over a 48 hour period and detail brain imaging including CT perfusion scanning to examine the ischaemic penumbra, CT angiography on admission and at 24-48 hours to document brain arterial patency with follow-up CT brain imaging to assess outcome infarct volume. The relationship between 48 hour blood glucose profiles, clinical outcome and imaging findings is then explored. The main findings of the thesis are summarized below. · Animal models of PSH have shown that hyperglycaemia exacerbates infarct volume in MCA occlusion models but studies are heterogeneous, and do not address the common clinical problem of PSH because they have used either the streptozotocin model of type I diabetes or extremely high glucose loads. · Animal models show that insulin has a non-significant and significantly heterogeneous effect on infarct growth. 3 · Clinical trials of insulin for post stroke hyperglycaemia have shown no benefit in terms of improved functional outcomes or mortality. Insulin is associated with an increased risk of hypoglycaemia. · In a historical cohort mean capillary blood glucose over 48 hours was more predictive of clinical outcome that admission blood glucose or two consecutive elevated glucose measurements. · A high proportion of acute stroke patients have a blood glucose level above 7mmol/L within 6 hours of onset. Different patterns of blood glucose levels define different populations. · Higher admission and mean glucose levels correlate with larger infarct volumes. Larger core perfusion lesion volumes are associated with a greater risk of mortality. Admission hyperglycaemia is more harmful than hyperglycaemia after 6 hours. · In patients with angiographic evidence of an arterial occlusion infarct volume varies significantly with glycaemic status. In some populations late hyperglycaemia is associated with better imaging outcomes. · Tandem occlusions are associated with bad outcomes after ischaemic stroke.

The aim of this thesis was to explore perceptual processing in individuals with autism and Asperger's syndrome, and to assess the extent to which the theory of weak central coherence could account for any abnormalities in this area. In Experiment 3:1 we presented individuals with autism with four illusions on a computer and asked them to adjust certain parts to appear the same. The results showed just as susceptible to illusions as those without autism on a computer task contrary to previous literature (Happe, 1996). In Experiment 3:2 we presented the same illusions on card and asked participants to judge whether parts of the stimuli were the same or different as in Happe's procedure. Our results showed that autistic populations succumbed to illusions regardless of whether they verbally judged or manually made adjustments to the stimuli. This ruled out the possibility that procedural differences could account for our failure to replicate Happe's findings. These results show that coherence is intact at low levels of perceptual processing in autism. Our second study (Experiment 4:1) explored whether individual differences in coherence may be able to explain why the results of Experiments 3:1 and 3:2 were not consistent with Happe's findings. We presented a battery of visuo-spatial tasks (block design, embedded figures, Rey complex figure test) and the visual illusion computer task to participants. Performance on these tasks was unable to predict susceptibility to visual illusions, suggesting that perception of illusions may not be related to weak central coherence. Our final investigation explored whether autistic populations were more inclined to rely on visual rather than semantic properties when asked to pair atypically coloured pictures (e. g. blue banana) with colour patches (e. g. yellow or blue). Those with autism relied on background knowledge like control participants choosing the semantically related colour. We then considered whether requiring the participants to name the object before selecting a colour may have influenced them to choose the semantic alternative in Experiment 5:2. Those with autism performed similarly to comparison groups choosing the semantic rather than the visual option. This demonstrated that background knowledge was just as salient to those with autism and Asperger's syndrome as those without autism.

Schizophrenia is a complex disorder, with several genes putatively associated with the pathogenesis of the disorder. A large genome-wide association study (O’Donovan et al. 2008) identified ZNF804A as a candidate gene for schizophrenia (meta-analysis p = 1.61 x 10-7). The association of the gene with schizophrenia (and bipolar disorder) has since been successfully replicated several times, confirming the association (Riley et al., 2010; Steinberg et al., 2010; Zhang et al., 2010, Williams et al., 2011). The aim of this thesis is to create and provide preliminary assessments of a mouse model of the murine form of ZNF804A, Zfp804a. A mutagenised DNA archive derived from mice treated with N-ethyl-N-nitrosourea (ENU) held at the MRC Mammalian Genetics Unit, Harwell, was screened for mutations in Zfp804a. Two mutations (C59X and C417Y) were selected for re-derivation based upon the estimated impact upon the protein. The mutations were backcrossed onto a C57Bl/6J background for three successive generations using a panel of genetic markers to aid selection for the highest level of C57Bl/6J congenicity (and therefore speed up the backcrossing process). G4 mice were tested in the study. Preliminary assessments of the fourth generation intercross cohort revealed, most notably, that the mice breed well, have no gross physical deficits and that male Zfp804aC59X/C59X mutants appeared less anxious than other groups in the elevated plus maze and performed better than other groups on the RotaRod. Initial indications show that Zfp804a may indeed influence behaviour and cognition however further work is necessary to expand upon these findings with larger samples.

It has been proposed that increased tissue iron concentration, which has been observed in certain regions of the brain in individuals with Alzheimer’s Disease (AD), could provide a marker for diagnosis through detection with MRI. This is investigated in this thesis using high field MRI to examine post mortem human brain tissue. It is shown here that by using data from multiple brain regions discriminant analysis can successfully differentiate between AD and control samples, even when no statistically significant differences are observed in individual brain regions. A unique set of complementary techniques was used to investigate iron content, R2 and R2* of tissue samples from the caudate nucleus, putamen, globus pallidus substantia nigra, amygdala and pons, from a set of three control and AD cases. The particulate iron content of the samples was investigated by SQUID magnetometry and was followed by iron quantification. A trend of increased particulate and total iron concentration was observed in the AD tissue compared to control, however this did not reach statistical significance in any brain region. High resolution MRI relaxometry at 9.4 T was carried out on tissue from the caudate nucleus, putamen, globus pallidus and substantia nigra using a custom design Bruker micro-imaging MicWB40 probe. As part of the work towards this PhD the probe was tested, and MRI relaxometry protocols optimised for high resolution (86 x 86 μm in plane, 150 μm slice thickness) mapping of tissue samples with high iron concentration. Again, no statistically significant differences were observed between AD and control tissue. However, discriminant analysis of these data (particulate or total iron or R2 or R2*) from multiple brain regions achieved differentiation between control and AD cases with 100% sensitivity and specificity for this small sample set. This demonstrates the potential clinical usefulness of MRI of measurements of non-haem brain iron to aid in disease diagnosis. Synchrotron X-ray fluorescence (SXRF) mapping of 30 μm thick sections, cut from the MRI samples, showed the relative concentration distribution of iron, copper and zinc in one AD and control sample from each brain region. Each metal was shown to have a distinct distribution. In particular, the inhomogeneity of iron concentration within individual brain regions, such as the putamen, was demonstrated. This may explain the wide variation in iron concentration reported in the literature for the same brain regions, and highlights the importance of close anatomical matching of samples when making comparisons. The ability of high resolution SXRF mapping to investigate the metal content within individual cells was demonstrated and used to show an increase in iron in individual AD neurons, in addition to the surrounding grey and white matter tissue. Spatially matched SXRF and MRI maps were used to demonstrate a strong, statistically significant linear relationship between tissue iron concentration and R2, R2* and R2’ at 9.4 T. The gradient of the linear relationship between iron and R2, agrees extremely well with the predicted gradient at this field, where the prediction was made by Vymazal et al. (1996) using MRI relaxometry at 0.05 to 1.5 T. To the best of my knowledge, this is the first time that this relationship has been quantified at 9.4 T, or at any field above 7 T. MRI at 14.1 T was carried out on low iron concentration regions (the pons and amygdala). Matched SXRF and R2* maps did not show a strong linear relationship between iron and R2*. The iron concentration in these regions is less than 50 μg/g and it was concluded that in tissue with low iron content, other tissue properties - such as water content - are dominating the value of R2*. This result was replicated with data measured at 9.4 T, when only tissue with an iron concentration of less than 50 μg/g was considered.

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.

Research suggests that people may hold positive explicit attitudes whilst holding negative implicit attitudes towards Lesbian and Gay (LG) people. While this seems evident amongst the general population, a previous systematic review (e.g. Boysen, 2009) only identified one study investigating explicit and implicit attitudes towards LG identities amongst counsellors. There are no similar systematic reviews using samples of psychologists, so this review aims to bridge that gap by conducting an analysis on studies completed between January 1990 and May 2013. In this review were included studies that: a) investigated attitudes of psychologists or psychologists-in-training towards LG people; b) included original data and findings; c) included comparison groups; and d) had been carried out in countries where homosexuality is not criminalised and where there is anti-homophobia legislation currently in place. Of the initial 933 studies identified, 18 met the main inclusion criteria. Designs were diverse and used a range of attitude measures. Only one study investigated implicit attitudes. Despite the diverse range of designs and measures it appears that positive attitudes to LG people may be conditional upon several factors, including gender, religiosity, socialisation, training, and level of education of psychologists. Training courses can potentially address such needs, but these need to be designed specifically to address LG topics, since general training on diversity topics may not promote positive implicit attitudes to LG people.

Measuring the quality of life (QOL) of individuals who live with long-term health conditions and illnesses has become more important in the absence of cure (Department of Health [DoH], 2013). Dementia is an intractable, progressive and terminal illness and recent research from the Alzheimer’s Society (2012) has highlighted that a large proportion of those with dementia report that they do not live well with dementia and indicates the impact of this on QOL. Historically, there was an assumption that individuals living with dementia, due to their cognitive impairment, were unable to comment and talk about their QOL, however more recent research has shown that this is not the case (Woods, 2012). There are a number of ways in which QOL can be explored. For example, a number of scales have been developed which can collect information through a variety of methods including: self-report (e.g., Dementia Quality Of Life: Brod, Stewart, Sands, & Walton, 1999), report by-proxy (e.g., Alzheimer’s Disease Health-Related Quality Of Life: Rabins, Kasper, Kleinman, Black, & Patrick, 1999), observational (e.g., Dementia Care Mapping: Kitwood & Bredin, 1992) or through a combination of such methods. Quality of life is highly subjective and this poses challenges for the collection of information about QOL. Numerous studies have highlighted the discrepancy between self-report and proxy report QOL scores (for a review see Ettema et al., 2005), and difficulties with observational methods such as observer bias are evident. Such observations suggest that self-report, where possible, is the gold standard for the measurement of QOL (Cahill & Diaz Ponce, 2011), although this is also not without difficulty (Ettema et al., 2005). Self-report scales of QOL for those living with dementia certainly have their utility; however, the application of such scales for those with advanced dementia seems variable. This may partly be due to the loss of verbal communication and understanding (Johnson et al., 2009). This is further explored as the main focus of the narrative review which discusses and critiques the body of research which has been published in the last ten years which has focused on the self-report of QOL. The studies reported in the review; three quantitative articles and three qualitative articles discuss different methods for the collection of information regarding QOL from those individuals living with dementia. Findings from the review suggest that whilst self-report scales for QOL can be highly useful and effective, it seems their most effective use is with individuals who have mild to moderate dementia (Karim, Ramanna, Petit, Doward, & Burns, 2008; Trigg, Jones, & Skevington, 2007a; Trigg, Skevington, & Jones, 2007b). Some studies included in the review reported the inclusion of participants with advanced dementia. However, it would seem that participants with advanced dementia are more likely to struggle answering some questions, leading to missing values: a similar observation was reported by Ettema et al. (2005). The review highlights, therefore, the growing need for accurate self-report measurement of QOL for those with advanced dementia. The qualitative studies reviewed indicated that interviews employing semi-structured or unstructured frameworks could be successful in gaining meaningful information from those living with advanced dementia about their QOL (Clare, Rowlands, Bruce, Surr, & Downs, 2008; Cahill & Diaz-Ponce, 2011). It seemed as though there were numerous advantages from using a qualitative method for collecting information from those living with dementia, and therefore this was the methodology adopted in the study. The empirical study invited participants to think about their QOL in the context of their diagnosis of dementia and to also consider their expected future QOL in light of advancing dementia. Given some of the challenges of communication from those with advanced dementia, the study recruited those with mild to moderate dementia to think about the future. Thinking about the future of dementia was anticipated to be highly emotive and potentially very distressing for participants, therefore through the use of one-to-one interviews, participants could be asked difficult and challenging questions sensitively. Participants described factors which impacted on their QOL such as reciprocal relationships, impact of skill loss and being supported by relatives. However, thinking about the future seemed more challenging for the participants. Some participants did express fear and uncertainty when asked to think about the future, and this was something that the majority of participants did not want to do. However, some participants expressed difficulties which their spouse or partner had when it came to considering the future and the terminal nature of the dementia. For some participants, having such conversations may be important and not doing so could be detrimental to QOL. This was discussed in the professional report for healthcare professionals, amongst other recommendations and clinical implications from the findings of the current study. Perhaps some of the fear and uncertainty generated by thinking about the future in terms of dementia, which the participants expressed, was related to stigma and misperceptions about dementia. There is little research on the impact of stigma for those living with dementia (Mukadam & Livingston, 2012), most of the research is focused on psychosis (schizophrenia) and therefore, exploring stigma in the context of dementia was considered as a direction for future research. In the Dementia Strategy, the DoH (2009) drew attention to stigma and the social awareness of dementia; this has remained a matter of interest for the current government, reflected in multimedia advertising and other campaigns. Future research based on the findings of the current study, might focus upon ways in which stigma and the misperceptions about dementia could be further explored.