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There is a good deal of information available from both neuropsychology and cognitive psychology to support the contention that visual short term memory is functionally segregable from spatial short term memory, within the context of a working memory approach to cognitive functioning. However, relatively little is understood about the precise functional relationships between these segregated components or about the method in which they operate. One suggestion has been that the spatial system operates sequentially, in line with the idea that its output is mediated by movement of the body, whilst the visual short term memory system operates a more parallel manner, retaining input from the visual array in a more holistic fashion. In the research reported in this dissertation, methods originally used to research short term memory in experimental animals were adapted for use in adult humans. This was done with the aim of firstly clarifying the patterns of segregation of visual - spatial working memory and secondly beginning to understand the functional architecture of those segregated components. A series of experiments were conducted, initially based on Logie and Marchetti's (1991) demonstration of visuo-spatial segregation and later based on developments of the delayed response (DR) short term memory task used in experimental animals. In all of these experiments an interference paradigm was used to investigate segregation, with the assumption that segregation would manifest itself in differential effects of interference. For example, visual interference should impair visual but not spatial memory task performance, and vice versa for spatial interference. The results of these experiments clearly demonstrated segregation or visual and spatial processing. Furthermore they support the idea that spatial memory is a sequential process and visual memory a parallel one. However it was also observed that sequentially and parallelism were not the sole specifications of the two systems: memory for the appearance and location of items was also important.

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Neuroimmune proteins are involved in a wide array of biological functions throughout brain development. Importantly, these molecular mechanisms regulate the activity-dependent sculpting of neural circuits during the critical period. Abnormal expression of these molecular mechanisms, especially in early development, is linked to the emergence of neurodevelopmental disorders. Despite having central roles in both normal and pathological conditions, very little is known about the lifespan expression of neuroimmune proteins in the human cortex. As studies exploring the relationship between inflammation and disease tend to rely on animal models, unpacking immune lifespan trajectories in the human brain will be essential for translational research. Furthermore, it will aid the development of timely and effective therapeutic interventions for neurodevelopmental disorders. In my thesis, I characterize the development of 72 neuroimmune proteins in 30 postmortem tissue samples of the human primary visual cortex. These samples cover the lifespan from 20 days to 79 years. I compare the developmental profiles of these immune markers to those of well-studied classic neural proteins including glutamatergic, GABAergic and other synaptic plasticity-related markers. Using a data-driven approach, I found that the 72 neuroimmune proteins share approximately eight developmental patterns, most of which undulate across the lifespan. Furthermore, I used unsupervised hierarchical clustering to show that the development of neuroimmune proteins in the human visual cortex varies from that of classic neural proteins. These findings facilitate a deeper understanding of human cortical development through two classes of proteins involved in brain development and plasticity. / Thesis / Master of Science (MSc) / The human brain develops across the lifespan. This ability of the brain to change and adapt to the environment is called plasticity and it is essential for normal brain functions, such as processing visual information. Immune proteins play important roles in the visual cortex- the brain region responsible for visual information processing. They help establish brain circuits in early development and regulate ongoing neural processes important to brain plasticity. In my thesis, I measure the expression of neuroimmune proteins to unpack their developmental patterns in the human visual cortex. I found that these proteins have fluctuating levels across development, with many displaying heightened expression levels in early childhood. Additionally, I found eight common trajectory patterns that were shared between the proteins. These findings enable a better understanding of how regulators of human brain development mature.

Genome wide association studies have provided evidence for a significant association between ZNF804A (zinc finger protein 804A) - specifically the intronic single nucleotide polymorphism (SNP) rs1344706 - and schizophrenia, but little is known about the function of the gene or the effects of the SNP. By studying post-mortem human brain tissue, I characterised ZNF804A immunoreactivity in adult and foetal human brain and investigated effects of diagnosis and rs1344706 genotype on ZNF804A mRNA and protein expression. Secondly, I looked in a large sample of healthy volunteers (n=922) at the effects of rs1344706 on brain structure using volumetry and voxel based morphometry (VBM). Furthermore, I recruited healthy volunteers who were either homozygous for the risk allele or homozygous for the non-risk allele (n=50). They participated in magnetoencephalography (MEG) and magnetic resonance (MR) sessions in which brain activity was measured during a working memory task, a visual processing task, and rest. Using magnetic resonance spectroscopy, also neurotransmitter levels were assessed. The experiments conducted for this thesis showed for the first time that ZNF804A immunoreactivity can be detected in both foetal and adult human brain and that it is mainly localised to layer III pyramidal cells, with a granular subcellular distribution throughout the cytoplasm. No effect of rs1344706 on mRNA and protein expression was found. In our structural MRI study, rs1344706 did not affect macroscopic brain structure as measured by volumetry and VBM, and given the large sample size, this seems a convincing negative. However, we did find that rs1344706 alters prefrontal-hippocampal connectivity, with increased connectivity being observed in risk homozygotes. Additionally, using MEG, we found an effect of ZNF804A genotype on hippocampal connectivity in the theta band (4-8Hz), with non-risk homozygotes displaying more connectivity. This finding provides a first clue as to the mechanisms that might underlie the previously observed effects of rs1344706 on prefrontal-hippocampal connectivity. Future studies will need to elucidate the actual function of the ZNF804A protein, in order to bridge the gap between the molecular and neuroimaging findings described in this thesis.

Neuropeptides are special in their expression profiles restricted to neuronal subpopulations and low tissue mRNA levels. Genetic, epigenetic and transcriptional mechanisms that define spatiotemporal expression of the neuropeptide genes have utmost importance for the formation and functions of neural circuits in normal and pathological human brain. This thesis focuses on regulation of transcription of the opioid/nociceptin genes, the largest neuropeptide family, and on identification of adaptive changes in these mechanisms associated with alcoholism as model human pathology. Two epigenetic mechanisms, the common for most cells in the dorsolateral prefrontal cortex (dlPFC) and the neuron-subpopulation specific that may orchestrate prodynorphin (PDYN) transcription in the human dlPFC have been uncovered. The first, repressive mechanism may operate through control of DNA methylation/demethylation in a short, nucleosome size promoter CpG island (CGI). The second mechanism may involve USF2, the sequence–specific methylation–sensitive transcription factor which interaction with its target element in the CpG island results in USF2 and PDYN co-expression in the same neurons. The short PDYN promoter CGI may function as a chromatin element that integrates cellular and environmental signals through changes in methylation and transcription factor binding. Alterations in USF2–dependent PDYN transcription are affected by the promoter SNP (rs1997794: T>C) under transition to pathological state, i.e. in the alcoholic brain. This and two other PDYN SNPs that are most significantly associated with alcoholism represent CpG-SNPs, which are differentially methylated in the human dlPFC. The T, low risk allele of the promoter SNP forms a noncanonical AP-1–binding element. JUND and FOSB proteins, which may form homo- or heterodimers have been identified as dominant constituents of AP-1 complex. The C, non-risk variant of the PDYN 3′ UTR SNP (rs2235749 SNP: C>T) demonstrated significantly higher methylation in alcoholics compared to controls. PDYN mRNA and dynorphin levels significantly and positively correlated with methylation of the PDYN 3′ UTR CpG-SNP suggesting its involvement in PDYN regulation. A DNA–binding factor with differential binding affinity for the T allele and methylated and unmethylated C alleles of the PDYN 3′ UTR SNP (the T allele specific binding factor, Ta-BF) has been discovered, which may function as a regulator of PDYN transcription. These findings emphasize the complexity of PDYN regulation that determines its expression in specific neuronal subpopulations and suggest previously unknown integration of epigenetic, transcriptional and genetic mechanisms that orchestrate alcohol–induced molecular adaptations in the human brain. Given the important role of PDYN in addictive behavior, the findings provide a new insight into fundamental molecular mechanisms of human brain disorder. In addition to PDYN in the dlPFC, the PNOC gene in the hippocampus and OPRL1 gene in central amygdala that were downregulated in alcoholics may contribute to impairment of cognitive control over alcohol seeking and taking behaviour.

The effects of mobile phone-like electromagnetic radiation on the human brain activity are examined. The research focuses on both radio frequency (RF) exposures and the much less studied low frequency (ELF) exposures (less than 40 kHz) arising from the battery operation of GSM handsets. The first single blind study recruited a small sample of twelve human volunteers. The eyes closed resting EEG activity is monitored after radio frequency exposure. With SAR levels of 2 W/kg, results reveal no statistical changes in any of the examined frequency bands for neither pulsed modulated RF signals nor continuous wave RF signals. In the second double blind study, a sample of 72 volunteers is recruited and an improved protocol comprised of separate pulsed RF, continuous RF and pulsed ELF exposures is employed. Exposures are delivered through a custom made handset capable of independent RF and ELF exposures. Findings include a reduced alpha band frequency activity during pulsed radio frequency and low frequency radiations exposures but no changes under the continuous RF radiation. Changes are present both during as well as after exposure, while greater changes are observed during exposures. The study of some non linear measures of the resting EEG revealed no changes under any of the active exposures. As the observed changes are very close to the normal EEG variation during resting conditions, their biological significance and health impact is not immediately obvious. However, their mere demonstration points to a low level interaction mechanism which may deserve further study.

The current study is the first to demonstrate that structural deficits in the Anterior Cingulate Cortex (ACC) of the human brain may play a role in reading ability. Recent imaging work has indicated that the ACC is activated by tasks involving modulation of the fronto-temporal networks during language processing tasks and may be involved in anticipatory reactions and response preparation during reading. This study investigated the relationship between ACC volumetric measurements and reading ability in a sample of 68 individuals nested within 24 families with and without reading disorders. This sample allowed for examination of the effect of the volume of the ACC on reading, while controlling for normally occurring fluctuations in the size of the ACC due to heredity and shared environment. Forty-five linear models were conducted in SPSS on all 68 participants using the brain measurements (ACC, ACC with Paracingulate (PaC), and Putamen, separately) as well as control variables (gender, FSIQ, family membership) as predictors of the outcomes variables related to reading achievement (GORT Passage, rate, and accuracy) and reading processes (CTOPP phonological awareness and rapid naming). The use of family membership as a random effect predictor together with the specific brain volume as a predictor allowed for the effect of family on reading outcomes to be accounted for while, explicitly accounting for any relationships that may exist between family and brain volume. Additional sets of measurements, with PaC, were included in the final analyses to address the inconsistent inclusion of this tertiary structure in earlier research. Finally, a control region (putamen) was included to rule out whole brain effects and improve the specificity of the findings. The most significant findings were that the results varied systematically with inclusion or exclusion of the PaC. Measurements including the PaC were statistically significant for reading achievement for the left side of the ACC as expected. However, for the ACC volume without PaC, it was the right side that was related to reading measures. Neither set of measurements of the ACC were predictive of group membership. The current study supported a role for the ACC in reading and suggests a standardized method for inclusion of the PaC in the volumetric analysis of the ACC. / text