This thesis investigated the role of the amygdala in social cognition by examining variability in social-perceptual abilities within the normal population and via experiments with individuals who have Asperger's syndrome (AS). I found that a significant proportion of men from the general population had a fear recognition deficit akin to that seen in patients with bilateral amygdala lesion and that poor fear recognition was associated with poor theory of mind ability and with reduced activation of the amygdala and associated areas of the 'social brain'. Further experiments suggested a mechanism for these impairments - reduced fixation of the eye region of the face - similar to that exhibited by patient SM, who has suffered bilateral amygdala damage. Overall, I found that AS subjects also had a fear recognition deficit when compared with matched controls. However, there was great variability in responses, with scores ranging from normal to severely impaired. Again, an eyetracking experiment showed that low fear recognition was related to a reduced amount of time spent fixating the eyes. Informed by recent neurodevelopmental models of amygdala involvement in autistic- spectrum disorders, I conducted psychological, neurophysiological and neuroanatomical experiments in order to examine the cause of this failure to attend to the eyes in some AS subjects. As a whole, the findings support a 'hyper-active amygdala model', in which social stimuli induce an aversive level of arousal and so are avoided. I suggest that inattention to social stimuli, which could have a number of possible aetiologies, might be at the heart of a general route to social cognitive impairment, which could be shared by several distinct populations.

Unplanned off-task thinking (mind wandering) is a common ephemeral experience which has recently received increased scientific and clinical attention. This thesis investigated continuity between unplanned thought and memory processes and sought to show that mind wandering may disrupt pleasurable experience in dysphoria. The literature review aimed to determine whether the constructs of involuntary autobiographical memory and retrospective mind wandering describe the same phenomenon. The memory literature suggested four predictions about the correlates of retrospective mind wandering. A review of 11 mind wandering studies found some support for the prediction that unplanned thoughts are less subject to executive control when they are retrospective. Predictions about the cueing, recall probability and content biases of retrospective mind wandering require further research. Contextualisation in the memory literature offers promise for better understanding the causes and content of mind wandering. The empirical paper tested the hypothesis that mind wandering is a causal mechanism of disrupted pleasure (anhedonia). An unselected sample of 49 participants underwent positive mood inductions with and without distraction, followed by a task training inhibitory control of negative material and repeated mood inductions. Negative distraction successfully increased mind wandering and reduced sadness repair from positive material but these attenuations were not altered by inhibitory control training. Longer training and more precise manipulations of mind wandering were suggested for future studies. The critical appraisal noted some of the challenges encountered in pursing the aims of the thesis, proposed some improvements to mind wandering measurement in light of recent theoretical developments and outlined how errors in affective forecasting for memories, encountered anecdotally during testing, might be studied empirically.

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Recent advances in molecular genetics have enabled generation of sophisticated genetically-modified mouse models to study specific molecules and their biological function in vivo. Here, I investigated biochemical changes in two different genetically-modified mouse lines with previously described learning and memory phenotypes. Firstly, I analysed biochemical changes in a mouse line carrying a threonine to alanine point mutation at Thr286 of alpha Ca2+/calmoduline-dependent kinase II (aCaMKII), which disenables this phosphorylation site. Autophosphorylation at Thr286 switches aCaMKII into an autonomous activity mode. The T286A mutant mice displayed changes in basal phosphorylation levels. In order to study biochemical changes after activity-dependent synaptic potentiation, an in vivo long-term potentiation (LTP) approach was established and validated by assessing activity-dependent changes in phosphorylation levels of well-characterised marker molecules including synapsin I and NR2B. Both aCaMKII and pCaMKII exhibited elevated levels of autophosphorylation after LTP stimulation in hippocampal area CA1 and dentate gyrus (DG). This finding indicates that pCaMKII may compensate for the loss of autonomous aCaMKII activity in T286A mutants. Furthermore, induction of LTP triggered phosphorylation of glycogen synthase kinase 3 (GSK3) at its inhibitory site suggesting a role for GSK3 in synaptic plasticity. Secondly, I investigated a transgenic (TG) mouse line expressing the cyclin-dependent kinase (Cdk5) activator protein, p25, a protein previously linked to some aspects of Alzheimer's disease (AD). The forebrain restricted expression of p25 started postnatally and stayed constant throughout the life-span of the TG mice. The expression of p25 triggered constitutive over-activation of Cdk5 in the TG mice. The p25 TG mice displayed age-dependent hyperphosphorylation of the microtubule-associated protein tail and age-dependent alterations in the processing of amyloid precursor protein (APP). Furthermore, p25-induced over-activation of Cdk5 led to inhibition of GSK3. This negative regulation of GSK3 was lost in aged p25 TG mice and correlated with the increased tau hyperphosphorylation. The levels of tau phosphorylation in aged p25 mice were reduced after treatment with lithium, an inhibitor of GSK3. These results indicate that GSK3 directly mediates tau hyperphosphorylation, whereas Cdk5 acts indirectly via inhibitory control of GSK3.

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