Autism spectrum disorders (ASD) are neurodevelopmental disorders with multiple neurobiological aetiologies, which could be genetic, structural, metabolic or immune-mediated. ASDs are diagnosed with deficits in social communication and restricted and repetitive behaviours, and are associated with sensorial atypicalities. 30% of cases have co-existing epilepsy. A series of in vitro, in vivo and post-mortem investigations were undertaken to examine sensory atypicalities in ASD. In vitro characterisation of hippocampal neuronal cultures using immunofluorescence demonstrated the presence of multiple cell types including neurons, astrocytes and microglia. The distribution of ion channels of the Shaker family and tumour necrosis factor α receptors in astrocytes and neurons were identified but not explored further. Neuroanatomical and neuropathological investigations of primary olfactory cortex, using post-mortem stereology, demonstrated a specific increase in glial cell densities in layer II, which was negatively associated with age in ASD. Increases in glia were also associated with symptom severity and often co-localised with the presence of corpora amylacea in layer I. Qualitative analysis of the olfactory tubercle demonstrated that corpora amylacea did not extend to this neighbouring region of the primary olfactory cortex in ASD. These changes were independent of co-existing epilepsy and not observed in epilepsy without ASD. Preliminary pilot studies of the hippocampus provided a stereological sampling strategy to quantify cell densities in future investigations of this area in ASD. Neurophysiological investigations using collected magnetoencephalography data demonstrated diminished occipital gamma oscillatory synchrony in ASD in a visual time perception task. This did not always predict behavioural outcome but was specific to ASD and could not be explained simply in terms of changes in task performance. Moreover, changes in oscillatory synchrony were associated with symptom severity. These observations in primary sensory domains in post-mortem tissue and in patients suggest possible novel mechanisms in ASD and extend knowledge of the neurobiological bases of these disorders.

Recurrent and intrusive distressing recollections of trauma are a hallmark symptom of Posttraumatic Stress Disorder (PTSD). The term ‘flashback’ is used in this thesis to refer to vivid, sensory perceptual (predominantly visual images), emotional memories from a traumatic event that intrude involuntarily into consciousness. Furthermore, intrusive image based memories occur in a number of other psychological disorders, for example, bipolar disorder and depression. Clinically, the presence and occurrence of flashbacks and flashback type memories are well documented. However, in terms of the neural underpinnings there is limited understanding of how such flashback memories are formed or later involuntarily recalled. An experimental psychopathology approach is taken whereby flashbacks are viewed on a continuum with other involuntary autobiographical memories and are studied using analogue emotional events in the laboratory. An initial review develops a heuristic clinical neuroscience framework for understanding flashback memories. It is proposed that flashbacks consistent of five component parts – mental imagery, autobiographical memory, involuntary recall, attention hijacking and negative emotion. Combining knowledge of the component parts helped provide a guiding framework, at both a neural and behavioural level, into how flashback memories may be formed and how they return to mind unbidden. Four studies (1 neuroimaging, 3 behavioural) using emotional film paradigms were conducted. In the first study, the trauma film paradigm was combined with neuroimaging (n = 35) to investigate the neural basis of both the encoding and the involuntary recall of flashback memories. Results provided a first replication of a specific pattern of brain activation at the encoding of memories that later returned as flashbacks. This included elevation in the rostral anterior cingulate cortex, insula, thalamus, ventral occipital cortex and left inferior frontal gyrus (during just the encoding of scenes that returned as flashbacks) alongside suppressed activation in the left inferior frontal gyrus (during the encoding of scenes that returned as flashbacks in other participants, but not that individual). Critically, this is also the first study to show the brain activation at the moment of flashback involuntary recall in the scanner. Activation in the middle and superior frontal gyri and the left inferior frontal gyrus was found to be associated with flashback involuntary recall. In the second study, control conditions from 16 behavioural trauma film paradigm experiments were combined (n = 458) to investigate commonly studied factors that may be protective against flashback development. Results indicated that low emotional response to the traumatic film footage was associated with an absence of flashbacks over the following week. The third study used a positive film to consider the emotional valence of the emotion component of the framework. Positive emotional response at the time of viewing the footage was associated with positive involuntary memories over the following week. The fourth study aimed to replicate and extend this finding, comparing the impact of engaging in two cognitive tasks after film viewing (equated for general load). Predictions were not supported and methodological considerations are discussed. Results may have implications for understanding flashbacks and involuntary autobiographical memories occurring in everyday life and across psychological disorders. Further understanding of the proposed components of the clinical neuroscience framework may even help inform targeted treatments to prevent, or lessen, the formation and frequency of distressing involuntary memories.

Anxiety and depression are highly prevalent diseases with common heritable elements, but the particular genetic mechanisms and biological pathways underlying them are poorly understood. Part of the challenge in understanding the genetic basis of these disorders is that they are polygenic and often context-dependent. In my thesis, I apply a series of modern statistical tools to ascertain some of the myriad genetic and environmental factors that underlie fear-related behaviours in nearly two thousand heterogeneous stock mice, which serve as animal models of anxiety and depression. Using a Bayesian method called Sparse Partitioning and a frequentist method called Bagphenotype, I identify gene-by-sex interactions that contribute to variation in fear-related behaviours, such as those displayed in the elevated plus maze and the open field test, although I demonstrate that the contributions are generally small. Also using Bagphenotype, I identify hundreds of gene-by-environment interactions related to these traits. The interacting environmental covariates are diverse, ranging from experimenter to season of the year. With gene expression data from a brain structure associated with anxiety called the hippocampus, I generate modules of co-expressed genes and map them to the genome. Two of these modules were enriched for key nervous system components — one for dendritic spines, another for oligodendrocyte markers — but I was unable to find significant correlations between them and fear-related behaviours. Finally, I employed another Bayesian technique, Sparse Instrumental Variables, which takes advantage of conditional probabilities to identify hippocampus genes whose expression appears not just to be associated with variation in fear-related behaviours, but cause variation in those phenotypes.

<p>The manifestations of early sleep disturbances on cerebrospinal fluid and their relations with early developmental competencies are understudied. Recent studies highlight cerebrospinal fluid disbursement as a potential factor associated with dysfunctions in brain development. With two studies, we explored sleep and extra-axial cerebrospinal fluid (EA-CSF) connection as a potential mechanistic pathway by which sleep dysregulation influences brain and behavior development. Specifically, we evaluated associations between (1) EA-CSF to total cerebral volume (EA-CSF/TCV) ratios, (2) parent-report of child sleep problems, and (3) social communication development in typical (Study 1) and atypical populations (Study 2). In typical infants, early sleep problems did not precede later elevated EA-CSF/TCV ratios or social-communicative competence. Elevated EA-CSF/TCV ratios were associated with impaired social communication skills, suggesting that a relationship between elevated EA-CSF/TCV ratios and social communication impairments exists regardless of neurological or sleep problems. In an atypical population with autism spectrum disorder (ASD), older children with ASD had similar EA-CSF/TCV ratios to a group of their typically developing peers. Sleep problems were negatively associated with EA-CSF/TCV ratios but positively associated with social-communicative impairments for children with ASD, highlighting the influence of sleep problems on both brain and behavioral outcomes in an atypical population. In both studies, EA-CSF volumes continue to increase during early development in the typically developing populations (but not later in the atypical sample), underlining its relevance as a marker of atypical processing. Recognizing the potential roles of EA-CSF in influencing several biosocial and behavioral aspects of development, we encourage researchers to continue to explore EA-CSF growth, especially during developmental periods of flux and transition. Future work with longitudinal data can also serve to explore sleep-related developmental changes in EA-CSF, in association with behavioral and phenotypic changes. </p>