Theses - Graduate Program in Neuroscience
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Item Open Access Age and gender alter synaptic proteins in zebrafish (Danio Rerio) models of normal and delayed aging(Bilkent University, 2017-07) Karoğlu, Elif TuğçeCognitive decline occurs during normal aging in some specific domains of cognitive abilities including but not limited to episodic memory, divided attention and executive functions, however, it is not a unitary decline since some cognitive domains, including vocabulary and implicit memory tend to be preserved and even improved at older ages. Normal aging is not associated with global and significant neuronal and synapse loss, yet subtle molecular alterations occurring in gene expression patterns, protein homeostasis, mitochondrial dynamics and hypofunction in the cholinergic system may account for the age related decline in some cognitive abilities. Additionally, males and females showed differential vulnerabilities against age-related alterations in the cognitive abilities, physiological integrity and subtle molecular dynamics. More direct relationships can be established between the age-related cognitive decline and subtle molecular changes by analyzing the elements of synaptic integrity, which could alter synaptic plasticity and result in the changes in learning and memory abilities. Post-synaptic 95 (PSD-95), gephyrin (GEP) and synaptophysin (SYP) are integral synaptic proteins and they could be attributed as indicators of excitatory post-synaptic, inhibitory post-synaptic and pre-synaptic integrities, respectively. The first aim of this study was to show effects of age and gender on the expression levels of PSD-95, GEP and SYP in young, middle-aged and old, female and male zebrafish cohorts. Significant age by gender interactions were revealed in the levels of PSD-95 and SYP. It was shown that PSD-95 and SYP levels tend to be preserved and increased in the female groups throughout the aging process, whereas, in male groups, expression levels of these proteins tend to be reduced at older ages. The second aim was to investigate whether ameliorating the cholinergic hypofunction might have beneficial effects on the aging-related protein expression alterations and check for sexually dimorphic patterns. For this aim old male and female zebrafish from a mutant line (ache), which has decreased levels of acetylcholinesterase and increased levels of acetylcholine, were compared with old male and female wildtype animals. In the ache old groups, significant increases in the expression levels of SYP and GEP were revealed compared to the wildtype, and also in the old ache females SYP expression was higher than the other groups. These studies emphasized the importance of gender and sexually dimorphic patterns in the context of aging andcholinergic manipulations could be a promising target of intervention to attenuate the effects of age-related synaptic alterations, which could have possible contributions to age-related cognitive decline. .Item Open Access Age related alterations of adult neurogenesis and astrocytes in Zebrafish (Danio Rerio)(Bilkent University, 2019-09) Ardıç, Narin IlgımBrain aging is marked by a decline in cognitive abilities and associated with neurodegenerative disorders. In order to identify appropriate interventions to change the course of brain aging and age-related neurological disorders, we should first understand the normal age-related changes. Previous studies claimed that there was a correlation between cognitive capacities and number of neurons. However, recent studies have shown no statistically significant change in total neuron number during healthy aging. Therefore, further studies are required to understand the reasons behind these changes in the brain. One possibility could be the age-related alterations in neuronal lineage and glial markers. Thus, this study aims to show the protein levels, distributions, and localizations of key neuronal lineage and glial markers, which include neural progenitor, early neuronal, immature neuron, and mature neuron and glial markers during healthy aging of the zebrafish brain. For this aim, we measured NeuN (Fox-3, Rbfox3, or Hexaribonucleotide Binding Protein-3), MAP-2 (Microtubule-associated protein 2), HuC (ELAV like neuron-specific RNA binding protein 3), DCAMKL-1 (Doublecortin-like kinase 1), and GFAP (Glial fibrillary acidic protein) with immunohistochemistry and western blot techniques. First, the immunohistochemistry technique was applied on two specific proliferation areas, pallium and optic tectum, to detect the changes in the number of neuronal lineages and glial marker. The results indicated no statistically significant changes between young and old groups. Secondly, we performed whole-brain immunohistochemistry of all markers and quantified every image by manually counting the positive signal. We found that aging did not have an effect on the distribution and expression of the markers, even in the whole brain. Finally, Western-blot was performed in whole brain lysates to compare neuron number and protein level changes. Western-blot results indicated an age-related statistically significant decline in immature neuron marker for specifically males and glial marker for specifically females. The protein level of neural progenitor marker showed the significant decline in males during aging but no change between two age groups. Results of the mature neuron antibody revealed that the protein levels were consistent through aging and did not show variation. Our results overall support the finding that the number of neurons and glia do not change during aging since the numbers of markers were not show statistically significant changes during the aging process in the proliferation areas of the zebrafish brain. However, protein levels showed changes between age and gender groups. Thus, this study shows that understanding changes in the number of cells need to count; protein level is not representative, and zebrafish is an appropriate model for brain aging studies.Item Open Access Age-dependent effects of short-term intermittent fasting and rapamycin treatment in Zebrafish (Danio Rerio) brain(Bilkent University, 2020-05) Birand, Ergül Dilan ÇelebiWorld populations are rapidly aging, and there is an urgent need to develop interventions that prevent or reverse age-related deterioration of health. To date, several approaches have been developed to extend health span. Among these, non genetic interventions have a higher potential to be utilized in translational studies. Caloric restriction (CR) and its pharmacological mimetic rapamycin, are two applications that have been shown to reliably extend life and health span across species. Despite a growing body of knowledge on how CR and rapamycin show their beneficial effects, their molecular mechanisms in the brain are not completely understood. Furthermore, most studies applied life-long CR, which is not suitable for translational research. To fill this gap, we investigated whether short-term durations of a CR approach intermittent fasting (IF) or rapamycin altered cellular and molecular markers of critical processes in the brain as well as metabolic parameters in the body. To assess how the age of the subjects affect the outcome of the treatments, we included young (6-10 months old) and old (26-31 months) zebrafish, which has recently emerged as a suitable model for gerontological research. Our results demonstrated that IF decreased whole-body glucose and cortisol levels, and increased neural progenitor marker DCAMKL1 in young and old animals. While this proliferation-promoting effect was preceded by suppression of mTOR activity in young, the upregulation of foxm1 and reduced autophagic flux as measured by LC3 II/LC3-I ratio were observed in old animals. Rapamycin, on the other hand, did not alter the metabolic parameters and induced entirely different molecular profiles at young and old ages. The most notable changes in young animals were reduced mTOR activity, LC3-II/LC3-I ratio and expression levels of a global proliferation marker PCNA. In old animals, the marker of activated astrocytes (i.e. GFAP) was decreased, indicating lower neuroinflammation, whereas excitatory-inhibitory balance as measured by PSD-95/Gephyrin ratio was shifted towards a more excitatory state. These results suggested that IF and rapamycin induced distinct metabolic profiles in young and old animals. Furthermore, there was an age dependent reciprocal relationship between proliferation and autophagy, which might be partly due to differential regulation of mTOR activity. Interestingly, rapamycin treatment was more effective in suppressing mTOR activity in young animals, and compared to IF. Nevertheless, these results suggested that rapamycin crosses the blood-brain barrier in zebrafish, and that short-term durations of IF or rapamycin were sufficient to alter the expression levels of key proteins involved in critical mechanisms in the brain.Item Open Access Alterations in the molecular properties of neural stem cells from aged brains and brain tumors(Bilkent University, 2017-06) Burhan, Özge PelinIt is known that new neuron formation in the brain continues throughout the life of an organism. In the adult human brain, it was proven that neurogenesis in the hippocampus is higher than expected, almost 700 new neurons are formed in a day. The formation of new neurons is supported by the stem cell subpopulation in the brain. With learning and the formation of new memories, the neuron production increases. However, changes in the cognitive abilities with advancing age are thought to be caused by the functional and molecular alterations in the stem cell populations. Molecular changes in neural stem cells throughout aging were found to be deterrents of the increased risk of cancer with age, such as tumor suppressor mechanisms. However, the activation and overlap of tumor suppressing mechanisms result in senescence in stem cells that have accumulated oncogenic mutations, which causes the stem cell pool exhaustion. It is thought that cancer cells acquire stem cell-like properties in order to have the unlimited proliferation and self-renewal properties, which are characteristics of both healthy and cancer stem cells. Neural cancer stem cells have the ability to produce glial and neural cells, like normal stem cells. The cancer stem cell subpopulations are implicated in the growth of tumor tissues. Hence, it is important to identify and characterize cancer stem cells and make a distinction between cancer and non-cancer stem cells. In this project, this issue was addressed by studying the marker expressions of brain tumor tissues obtained from humans, which confirmed that the cancer cells do express stem cell and progenitor cell markers, such as Sox2 and Vimentin. The presence of mature neurons was also established by the mature neuronal marker NeuN. In order to determine whether these stem cells may be different in young and old subjects, a study was also carried out in young and old zebrafish neural stem cells in order to identify the expression differences between the groups. The presence of proliferating stem cells and differentiated cells were identified in cell culture. This analysis of neural stem cells in old and young zebrafish revealed 18 differentially-expressed genes. The results indicated a higher differentiation rate in old zebrafish stem cells, which may be due to the increased loss of neural cells in the old zebrafish brain. The development of markers that could be widely used for the diagnosis of cancer and the identification of cell types is important. For reliable diagnosis and identification of cancer cells, multiple cellular markers are used. Hence the distinction of cell types based on light scattering differences would speed up the process of diagnosis, and the elimination of marker used for the distinction of cell types would be beneficial. The final project mentioned in this thesis involves the analysis of C6 (rat glioma) cell line for scattering properties and cell cycle arrest. A general method for definition of a scatter data interval for C6 cells in different stages was developed and can be applied to other cell types and diseases. These studies show that the proliferation and stem cell markers’ expressions differ between cancer and healthy stem cells, and the expression of neuroprotective genes is differentially upregulated in old zebrafish neural stem cells compared to the young. This data could contribute to the knowledge on normal and cancer stem cell expression differences, as well as how age affects the expression, and supply information required for the development of a cancer stem cell identification and targeting methods.Item Open Access Analysis of differentially expressed genes in bipolar disorder: transcriptomic signature of adolescence and young adulthood in working memory-relared area(Bilkent University, 2020-11) Şen, RabiaBipolar disorder (BD) is a heritable severe illness. One of the indications of BD is working memory (WM) impairment which is a heritable cognitive trait. The aim of the current study is to identify the transcriptomic level developmental biomarkers of BD in WM-related brain regions. We based our analysis on adolescence and young adulthood (AYA), the critical period for both BD and cognitive development. We have chosen 4 publicly available microarray datasets from Gene Omnibus database for which one is derived from healthy controls and three from bipolar disorder patients. We compared different developmental periods of the brains of normal subjects to determine healthy brain development at the transcriptomic level. After applying the same method to detect bipolar development to show differences between BD and healthy brains. We followed these comparisons in two steps; on gene-level analysis and geneset level analysis. Next, we identified common genes and pathways from the results of different analyses. As a result of this comparison, while six genes were identified differentially expressed, we observed 5 Gene Ontology (GO) genesets shown different regulation patterns in bipolar and healthy brains. The literature review has been shown that the significant biological pathways might be influenced by the treatment.Item Open Access Analysis of movement disorder-related genes following knockdowns of ANO10, WDR81, and VLDLR in zebrafish (DANIO RERIO)(Bilkent University, 2018-06) Şengül, Göksemin FatmaMovement Disorders are the neurological symptoms that cause alterations in normal motility, posture and muscle tone. Certain brain areas, such as the cerebellum, mediate correct motor control and functioning. When defects or congenital lesions occur in the cerebellum, neural disruption in motor coordination causes the development of a particular movement disorder known as cerebellar ataxia. The focus of this study was to examine how three genes of interest (ano10, wdr81, vldlr), contributing to multiple varieties of cerebellar ataxias, influence one another and other genes that are associated with this disorder. Mutations in vldlr and wdr81 are associated with Cerebellar Ataxia Mental Retardation Disequilibrium Syndrome type 1 and type 2 (CAMRQ1 and CAMRQ2), respectively, whereas mutations in the ano10 gene is responsible for the development of Autosomal Recessive Cerebellar Ataxia Type 3 (ARCA3). In this work, five key scientific findings were reported. Firstly, in silico analysis predicted a common Ca2+ activated Casein Kinase 2 (CK2) domain in the protein sequences of the genes of interest and also predicted a common interacting UBC protein. These predicted interactions, a common CK2 domain and a UBC interacting protein may explain the observed neurodegenerative phenotype in cerebellar ataxia. Secondly, the transcript level analysis (qPCR and RNASeq) of ano10a, wdr81 and vldlr using zebrafish embryos collected from early embryonic and late larval stages showed that the three genes were expressed relatively higher at 1 hpf, 2 hpf and 5 hpf developmental stages than others and may suggest their importance in developmental processes. Additionally, the comparison of the expression patterns of ano10a, wdr81 and vldlr during early embryogenesis indicated that three targeted genes were co-localized at diencephalon, midbrain (optic tectum) and cerebellum. These spatiotemporal results may restrict the involvement of these three genes selectively in early neurodevelopmental processes. Thirdly, this study also examined the expression level analysis of three targeted genes in 12 different adult tissues in a sexually dimorphic manner. Findings showed that genes of interest were expressed significantly higher at the eyes, brain and gonads (p-values < 0.05). Moreover, the gender specific examination in the 12 adult tissues revealed that ano10a and wdr81 expression differed significantly at eyes, gills, liver and gonads (p-values < 0.05) whereas, vldlr gene expression was significantly different at swim bladder and gonads in male and female individuals (p-values < 0.05). Fourthly, the clustergram analysis indicated that three genes of interest were grouped within close families with each other and 9 additional cerebellar ataxia associated genes and may imply that targeted genes alter functions in the converging pathways. Finally, results from the clustergram analysis helped to design and carry out a study knocking down the expression of ano10a, wdr81 and vldlr separately with MO antisense technology to examine the effect of the silenced mRNA on the expression levels of each other and 9 other highly correlated cerebellar ataxia-related genes. Single MO injections caused the significant upregulation of all investigated genes especially at 72 hours after/post injection (hpi) (p-values < 0.05) when ano10a transcript was silenced suggesting either an activated compensatory mechanism or activated alternative disease specific cascade molecules in response to its absence. Taken together, the outcomes of functional knockdowns can pave the way for the development of novel therapeutic targets using inhibitors or antagonists of activated cellular pathway components or the enhancers of downregulated genes to prevent or at least slow down the progression of not only cerebellar ataxia but also several other neurodegenerative disorders.Item Open Access Arithmetic and temporal transformations of working memory activation in subjects prone to psychosis(Bilkent University, 2018-09) Baş, TimuçinWorking memory (WM) deficit is a well-studied cognitive impairment in psychosis which is stemming from various developmental abnormalities containing neurobiological heterogeneity. Recently, many studies have concluded that the WM impairment is a symptom which manifests itself before the onset of the disorder, but these studies mostly focused on the individuals at clinically high risk. The mild proneness to psychosis which develops during the adolescent period is not well understood and how the working memory is affected due to mild proneness to psychosis has not been elucidated heretofore. In this research, we aimed to examine the association between the mild proneness to psychosis and working memory processing. Thirty-two individuals were split in half as mildly prone to psychosis and not prone to psychosis based on the Structured Interview for Schizotypy (SIS-R). Each participant performed a robust working memory task which consists of computational and temporally varying information loads. The data were collected via a magnetic resonance imaging (MRI) scanner and analysed by applying a general linear model to detect altered working memory activations due to proneness to psychosis. We have observed that the processes requiring manipulation and rapid updating of the information are associated with a large network of prefrontal cortex and superior parietal lobule. The finding of this study suggests that the mild proneness to psychosis has affected the working memory weakly and that the alterations demonstrated in the prefrontal cortex and parietal lobules may be clinically relevant to psychosis.Item Open Access Audiovisual interactions in time and spatial grouping principles of vision(Bilkent University, 2016-10) Öğülmüş, CansuMultisensory integration is often studied with intermodal con ict where either visual input dominates and alters the percept of simultaneous auditory input or the other way around. For instance, when put in con ict, visual stimuli can drive the perception of where a sound originates (spatial ventriloquism) [1, 2] whereas auditory stimuli can drive the perception of when visual events occur (temporal ventriloquism) [3, 4, 5] .These interactions make adaptive sense given the auditory system´s superior temporal resolution and the visual system´s superior spatial resolution [6]. Moreover, it was found that temporal ventriloquism can change the perceived speed of visual motion [7]. By taking advantage of this in uence of auditory timing on perceived speed, we investigated how audiovisual interactions in time (i.e., temporal ventriloquism) are modulated by the spatial grouping principles of vision. In our experiments, we manipulated spatial proximity, common fate and uniform connectedness between moving ashes. Observers compared the speed of motion between different auditory timing conditions. Our results revealed that auditory in uences on perceived speed were significantly modulated by only uniform connectedness. More specifically, we found that auditory effects on vision was significantly less when a horizontal gray connecting bar grouped multiple sequential moving ashes. When horizontally placed moving ashes were grouped with a vertical connecting bar, the degree of auditory in uences in time was significantly stronger compared to not grouped (control) and horizontal connecting bar conditions. The effect of auditory clicks on single apparent motion grouped with horizontal connecting bar was smaller relative to the not-grouped condition. In addition, our analysis on EEG activities revealed consistent trends in agreement with the behavioral results. Audiovisual interaction patterns were observed both earlier (around P1) and later (around N1 and P2). Less auditory capture over the horizontal connecting bar condition relative to the vertical connecting bar condition was observed around 50-100 ms (P1) on the frontal and temporal channels and around 200-300 ms (N1) on the frontal, central, temporal and occipital-parietal channels. The larger effect of sound over the single apparent motion without connecting bar condition was observed around 50-100 ms and 200-300 ms on the central channels and 200-300 ms on the occipital-parietal channels. The difference between the individual effects of inner and outer sound conditions was found to be less for the horizontal connecting bar condition relative to the vertical connecting bar condition over the frontal, temporal, central and occipital-parietal channels while less individual effects of the inner and outer sound conditions on the single apparent motion with horizontal connecting bar condition relative to the without connecting bar condition was only observed over the central channels and late time intervals of the occipital-parietal and temporal channels. Overall the individual effects of both sound conditions were consistently similar on the horizontal connecting bar condition (compared to the vertical connecting bar condition) for all ROIs and on the single apparent motion with horizontal connecting bar condition (compared to the no-connecting bar condition) over the central channels. In general, our findings here suggest that temporal ventriloquism effects exist in different spatial grouping conditions of vision, but they can be also modulated by certain intra-modal grouping principles such as uniform connectedness.Item Open Access Behavioral and computational investigation of the effect of prior knowledge on visual perception(Bilkent University, 2021-01) Ürgen, Buse MerveVisual perception results from the dynamic interaction of bottom-up and topdown processes. Top-down prior knowledge and expectations can guide us to predict upcoming events and even determine what we see in an ambiguous or noisy sensory stimulus. Despite the well-established facilitating effects of expectations on recognition or decision-making, whether and how early sensory processes are affected by expectations remain unclear. This dissertation attempts to investigate the effect of expectations on early visual processes. To this end, we used behavioral experiments to examine the effects of expectation on visual perception at the threshold level and implemented a recursive Bayesian model and a recurrent cortical model to unravel the computational mechanisms underlying those effects. In the behavioral experiments, we systematically manipulated expectation’s validity in separate sessions and measured duration thresholds, which is the shortest presentation time sufficient to achieve a certain success level. Our behavioral findings showed that valid expectations do not reduce the thresholds, rather unmet expectations lead them to increase. Next, using a recursive Bayesian updating scheme, we modeled the empirical data obtained in the behavioral experiments. Model fitting showed that higher thresholds observed in the unmet expectations are not due to a change in the internal parameters of the system. Instead, additional computations are required by the system to complete the sensory process. Finally, within the predictive processing framework, we implemented a recurrent cortical model to explain the behavioral findings and discuss possible neural mechanisms underlying the observed effects. The cortical model findings were in agreement with the Bayesian model results, revealing that longer processing is needed when expectations are not met. Overall, the computational models that are proposed in this study provide a parsimonious explanation for the observed behavioral effects. The proposed experimental paradigm and the computational models offer a novel framework that can be extended and used in other stimuli, tasks, and sensory modalities.Item Open Access Behavioral and neural investigation on the effect of spatial attention on surround suppression(2023-09) Kınıklıoğlu, MerveWhen a visual stimulus is presented together with other stimuli surrounding it, behavioral sensitivity and neural responses may change, often reduce, compared to when the same stimulus is presented alone. This is commonly referred to as center-surround interaction or surround suppression, and it is one of the most fundamental mechanisms in biological vision. It is well documented that in motion perception, center-surround interaction is affected by the size and contrast of the stimulus. As the size of a drifting grating increases, motion direction discrimination performance, as well as neural activity in one of the main cortical motion processing areas, medial temporal complex (MT+), decreases if the grating has high contrast (surround suppression). Whereas, when the size increases within certain limits, both the discrimination performance and the neural activity in MT+ may increase if the grating has low contrast (surround facilitation). On the other hand, spatial attention is known to modulate surround suppression both in humans and non-human animals with static stimuli. No previous study, how-ever, has directly and systematically investigated the effect of the spatial extent of attention on surround suppression in human motion perception. The studies presented in this dissertation aim to investigate the effect of the extent of spatial attention on center-surround interaction in visual motion processing. In our experiments, we used two attention conditions and a novel stimulus design, where a ‘center’ and a ‘surround’ drifting grating were presented to the participants. Under one of the attention conditions, which we call the ‘narrow-attention’ condition, participants performed a task that limited their attention to the central part of the stimulus. Under the other attention condition, which we call the ‘wide-attention’ condition, participants performed tasks that required them to extend their attention to both the center and surround gratings. Using this experimental paradigm, we measured motion direction discrimination thresholds behaviorally and cortical activity with fMRI. Behaviorally, we found increased thresholds, that is, stronger surround suppression, under the wide attention condition. In the hu-man homolog of MT+ (hMT+), we found that increasing the spatial extent of attention leads to reduced cortical responses, that is, to stronger neural suppression. This was not the case for the activity in the primary visual cortex (V1). Finally, we show that a parsimonious computational model that incorporates spatial attention and response normalization can successfully predict the response patterns in hMT+ and V1. Furthermore, the model could provide a link between cortical responses and behavioral thresholds. Overall, our findings and analyses showed that the behavioral effect can be successfully predicted by hMT+ activity. These results reveal the critical role of spatial attention on surround suppression, namely that surround suppression in motion perception becomes stronger with a wider attention field, and reveal possible cortical mechanisms underpinning the effect.Item Open Access Behavioral and neural investigation on the effects of prior information on biological motion perception(Bilkent University, 2023-07) Elmas, Hüseyin OrkunThe capacity to understand the actions of others, a cognitive phenomenon known as biological motion perception, is crucial for humans. Recent research demonstrates that biological motion is processed distinctively compared to the motions of inanimate objects. A dedicated brain network for processing biological motion and actions has been uncovered through fMRI studies. M/EEG studies have revealed time windows within which biological motion processing occurs. Despite these findings, a comprehensive understanding of the fundamental mechanisms driving biological motion perception, especially the effects of top-down processes, and the temporal dimension of these effects still remain unexplored. Recent evidence in visual perception suggests that prior knowledge and expectations affect visual perception; however, the generalizability of these effects to socially important stimuli, such as biological motion, is still unknown. This study aims to illuminate the effects of prior information on the behavioral and neural mechanisms of biological motion perception. To this end, we conducted a series of behavioral experiments and an EEG experiment to investigate the effects of prior information on biological motion perception. Through our behavioral experiments, we found that prior information influences the individuation process of biological motion, albeit conditionally. Specifically, this influence is observed only when the cue carries information about the type of action in the biological motion stimuli, and the reliability of the cue is high, at 75%. Our EEG experiment demonstrated that correct and incorrect prior information affects the temporal dimension of biological motion perception, suggesting an early effect of prior information during biological motion processing. More-over, a comparison of the temporal generalization matrices suggested that correct prior information accelerates biological motion perception by accelerating the for-mation of related representations in the brain relative to the neutral condition. Additionally, the temporal generalization analysis results illustrate a sequence in representations within brain activity: the representation of location information precedes the representation of action type of biological motion. These results suggest that computational models, developed to model the underlying mechanisms of biological motion perception, should consider the implications of predictive processes and their temporal dimension. Furthermore, these findings support the applicability of predictive models to not only low-level stimuli but also to higher-level stimuli.Item Restricted Behavioral display of lumbar curvature in response to the opposite sex(Bilkent University, 2017-06) Şenveli, ZeynepThe aim of this thesis was to investigate the hypothesis that women adjust their lumbar curvature to approach the suggested biomechanical optimum of 45.5 degrees in response to the presence of an attractive member of the opposite sex. The experiment was designed to examine the relationship between a) participants’ ratings of an attractive male confederate and the displayed change in deviation from the optimum displayed by women, and b) participants’ ratings of the attractive male confederate and the displayed change in the absolute degree of lumbar curvature, both while controlling for potential confounds such as participants’ self-perceived physical attractiveness, self-esteem, personality traits, and sociosexual orientation. Initial statistical analyses revealed a significant change in participants’ lumbar curvature pre- to post-exposure to the attractive male confederate. Subsequent analyses to examine the nature of the change indicated that socio-sexual orientation reliably predicted the change in lumbar curvature, but not the change in deviation from the optimum. The remaining variables predicted neither the change in lumbar curvature nor the change in deviation from the optimum significantly. This study is aimed at increasing our understanding of the behavioral display of lumbar curvature for self-promotion purposes in response to the presence of opposite sex.Item Embargo CAP-RNAseq: an online platform for RNA-seq data clustering, annotation and prioritization based on gene essentiality and congruence between mRNA and protein levels(Bilkent University, 2024-04) Özdeniz, Merve VuralIn recent years, there has been a remarkable growth in the application of RNA-seq in both clinical and molecular biology research contexts. The analysis and interpretation of these RNA-seq data demands a good knowledge of bioinformatics. Many different applications are available to perform the analysis, but more comprehensive applications are needed, especially for researchers without coding experience. Therefore, I developed an all-in-one novel RNA-seq analysis tool, CAP-RNAseq (http://konulabapps.bilkent.edu.tr:3838/CAPRNAseq/), which provide valuable analysis for co-expression cluster prioritization and annotation. CAP-RNAseq in particular performs clustering of the genes based on their expression patterns, annotates mirror clusters that display inverse patterns with a network-based visualizations before prioritization of clusters and/or genes based on "gene essentiality", protein levels and the degree of congruence between mRNA and protein levels of genes. Furthermore, for illustration of the use of CAP-RNAseq in this thesis, I reanalyzed a number of published RNA-seq datasets and identified novel pathways modulated by NTRK2 overexpression (GSE136868) in neural stem cells and also showed significance of the essential genes/pathways in senescent cell clearance focusing on NTRK2 (fibroblast; GSE190998) and THBD (Huh7, GSE228941) siRNA models. In addition, I analyzed our lab’s novel RNA-seq data obtained from breast cancer cell lines in CAP-RNAseq; and the findings revealed a) the complex associations between steroid hormones; Drospirenone, Aldosterone, and Estrogen in hormone positive T47D and mineralocorticoid receptor-overexpressing MCF-7 cells; and b) significant differences in essential and non-essential gene expression of the isogenic MCF7 cells overexpressing wildtype or mutant TP53. I also studied a public breast cancer dataset (GSE201085) demonstrating CAP-RNAseq’s ability to identify novel breast cancer markers exhibiting high mRNA-protein level correlations. In conclusion, this thesis not only demonstrates the use and power of CAP-RNAseq as a tool to identify essential genes and pathways by analyzing RNA-seq data, but also provides new insights into the roles of essential genes in glioma, senescence and breast cancer.Item Open Access Changes in FMRI resting state networks due to audiovisual association induced effects on visual motion perception(Bilkent University, 2016-08) Yıldırım, Fazilet ZeynepAssociative learning, the process by which an association between two stimuli or a behavior and a stimulus is learned, is one of today's exciting and important topics of neuroscience. The in uence of multisensory associations on perceptual experience has revealed unexpected levels of sensory plasticity in the adult brain. By using an audiovisual association paradigm, we designed experiments to assess motion perception and BOLD activity under various associative learning conditions. Eleven subjects (3 males) participated in the audiovisual association training followed by resting state fMRI scans. Before and after the association training, random-dot motion with varying coherence values and static tones of distinct frequencies were presented. Subjects were required to indicate the direction of random-dot motion. During the association phase, random-dots moving up or down with 100% coherence was paired with either high or low frequency static tone. The behavioral data showed that the perception of random-dot motion with low coherence was signi cantly changed in favor of exposed audiovisual association. The analyses on resting state functional data indicated that identi- ed canonical networks (i.e., visual, auditory, sensory, motor, executive, memory, and default mode) did not di er signi cantly between pre- and post- association training, and inter-hemispheric coherence values between early stage visual motion areas were not increased. On the other hand, the connectivity strength between auditory and visual networks increased signi cantly after the acquired audiovisual association. Accordingly, these ndings suggest that even brief association training can lead to changes in connectivity between low-level sensory areas.Item Open Access Characterizing surround suppression in motion direction perception(Bilkent University, 2021-06) Kurt, Aslı GülVisual perception is often achieved by surround modulation mechanisms, which help us pool individual information in our visual field. This mechanism is also prominent in motion perception, namely motion discrimination. A center-surround antagonistic organization aids motion perception using these modula-tion mechanisms, which are facilitation or suppression. Decisions to which modu-lation type will take place are usually manipulated by changing size and contrast of drifting Gabor disc stimuli. Because a systematic investigation of these mech-anisms is not conducted in prior research, we have used three different types of stimulus (small disc, annular, and large disc grating) to see whether there is a fa-cilitative or suppressive pattern between duration thresholds of these stimuli. To achieve this, we performed a behavioral study, that would assess motion discrim-ination thresholds of human participants for these stimuli via adaptive staircase procedures. Then, we looked for three possible pooling regimes by comparing duration thresholds of small disc-annular-large disc grating stimulus sets: effi-cient or inefficient (weak or strong suppression) pooling. We found that duration thresholds of large disc gratings were almost greater than small disc or annular gratings almost all the time in both contrast levels, which indicated a strong sup-pression. We have also conducted simulations of divisive normalization models and observed that modulation mechanisms were more prominent in simulated duration thresholds using MT parameters from literature than V1. Although previous literature suggests that MT region produces facilitative or suppressive effects within itself, we are not able to postulate a specific brain region creating strong suppressive pooling we observed in our behavioral data. This is why this study is a critical next step for future neuroimaging studies.Item Open Access Co-expression pairs and modules (CoEX-PM): a shiny application and an example case study on chromogranins(Bilkent University, 2018-09) Kaya, TuğberkGene expression signatures have been proved to be effective biomarkers of tumorigenesis and metastasis especially when alternative methods are inconvenient or ineffective. Nevertheless, handling very large datasets obtained via high-throughput protocols to extract gene expression signatures may prove challenging. A great number of software packages that facilitate such analyses have been written in R programming language are publicly available and free. However, the relatively steep learning curve that is required to use R proficiently prevents the utilization of these packages. I have developed the Shiny application Co-expression Modules and Pairs (CoEX-PM) using R programming language and the R package shiny. The CoEX-PM application handles human Affymetrix microarray data and enables users to generate pairwise correlation plots, conduct meta-correlation analysis with user-selected GEO datasets along with co-expression module generation by WGCNA program for genes of interest. The CoEX-PM application provides the user with a GUI, therefore, does not require any coding knowledge to perform the analyses. Pheochromocytoma (PCC) and neuroblastoma (NB) are neural-crest derived tumors, common in adults and children, respectively and are both associated with high-rate of morbidity and mortality. In addition, both tumor types display neuroendocrine tumor (NET) characteristics. Chromogranin A (CgA) has been linked with NETs as a moderately sensitive and non-specific tumor marker. The chromogranin family consists of up to seven members, three of which are chromogranin (CgA), chromogranin B (CgB) and secretogranin II (SgII) or occasionally named as chromogranin C (CgC). However, it is not known whether chromogranin/secretogranin family members are differentially co-expressed in PCC and NB. Here, I investigate the degree of co-expression in gene networks by analyzing gene expression signatures of the chromogranin/secretogranin paralogous gene family using CoEX-PM application on neuroendocrine tumor datasets. The findings indicate presence of concise and highly co-expressed functional components in PCC and NB driven by chromogranin expression signatures.Item Open Access Comparing the performance of humans and 3D-convolutional neural networks in material perception using dynamic cues(Bilkent University, 2019-07) Mehrzadfar, HosseinThere are numerous studies on material perception in humans. Similarly, there are various deep neural network models that are trained to perform different visual tasks such as object recognition. However, the intersection of material perception in humans and deep neural network models has not been investigated to our knowledge. Especially, the importance of the ability of deep neural networks in categorizing materials and also comparing human performance with the performance of deep convolutional neural networks has not been appreciated enough. Here we have built, trained and tested a 3D-convolutional neural network model that is able to categorize the animations of simulated materials. We have compared the performance of the deep neural network with that of humans and concluded that the conventional training of deep neural networks is not necessarily giving the optimal state of the network to be compared to the performance of the humans. In the material categorization task, the similarity between the performance of humans and deep neural networks increases and reaches the maximum similarity and then decreases as we train the network further. Also, by training the 3D-CNN on regular, temporally consistent animations and also training it on the temporally inconsistent animations and comparing the results we found out that the 3D-CNN model can use spatial information in order to categorize the material animations. In other words, we found out that the temporal, and consistent motion information is not necessary for the deep neural networks in order to categorize the material animations.Item Open Access Cortical processes underlying attentional modulations of dynamic vision(Bilkent University, 2022-09) Çatak, Esra NurVisual attention is one of the most fundamental cognitive functions guiding and influencing a various number of processes. However, how different neural mechanisms are modulated by selective attention to process information is still subject to debate. Utilizing electroencephalography (EEG), the current thesis focused on understanding the time course of visual information processing and its neural underpinnings with paradigms that operate in different attentional modes, such as visual masking, attentional load, and transparent motion design. First, we aimed to understand the role of spatial attention in information processing and its possible interactions with metacontrast masking mechanisms. The behavioral results revealed an interaction effect that suggests differential effects of spatial attention on metacontrast masking. The following EEG analyses revealed significant activation due to masking and attentional load on early negative components located over occipital and parieto-occipital scalp sites, followed by a late positive component centered over centro-parietal electrodes. These findings suggest that the effect of spatial attention may have distinct characteristics at different stages of sensory and perceptual processing regarding its relationship with metacontrast masking. Secondly, by employing a novel variant of transparent motion design with color and motion swapping, we aimed to isolate the object-based cueing effect from a possible feature-based explanation in both psychophysical measures and neural activities. Our results demonstrate that the behavioral effects of attentional cueing survived feature swaps, providing evidence for an object-based attention mechanism. We also observed event-related potential correlates of these object-based selection effects in the late N1 component range, over occipital and parieto-occipital scalp sites, significantly associated with the variation in behavioral performance. Our findings provide the first evidence of the role of the N1 component in object-based attention in this transparent-motion design under conditions that rule out possible feature-based explanations. Taken together, the present results highlight the substantial effects of selective attention on the processing of visual information after the initial entry of information into the visual system and before the completion of its processing.Item Open Access Design and application of nerve growth factor-β binding peptide nanofibers for neural regeneration(Bilkent University, 2016-11) Orhan, ZeynepPromotion of neurite outgrowth is an important limiting step for the regeneration of nerve injury and depends strongly on the local expression of nerve growth factor (NGF). Rational design of bioactive materials is a promising approach for the development of novel therapeutic methods for nerve regeneration, and biomaterials capable of presenting NGF to nerve cells are especially suitable for this purpose. This thesis describes development of nanofibrous peptide amphiphile (PA) nanofibers capable of promoting neurite outgrowth by displaying high density binding epitopes for NGF. The high-affinity NGF-binding sequence was identified by phage display and combined with a beta-sheet forming motif to produce a self-assembling PA molecule. Our results revealed that the bioactive nanofiber had higher affinity for NGF compared to control nanofiber and in vitro studies showed that the NGF binding peptide amphiphile nanofibers (NGFB-PA nanofiber) significantly promote the neurite outgrowth of PC-12 cells. In addition, the nanofibers induced differentiation of PC-12 cells into neuron-like cells by enhancing NGF/high-activity NGF receptor (TrkA) interactions and activating MAPK pathway elements. The first time with this study a seven amino acid phage display peptide library was utilized for high affinity epitope screening for NGF, the NGF binding sequence was incorporated into peptide amphiphile structure, and the effect of NGF binding material on differentiation pathway of NGF was analyzed. This material will pave the way for development of new therapeutic agents for nervous system injuries.Item Open Access Development of bioactive peptide nanofibers for intervertebral disc regeneration(Bilkent University, 2017-08) Uysal, ÖzgeLower back pain (LBP) and neck problems are the most common orthopedic diseases worldwide, and the main reason behind LBP is intervertebral disc degeneration (IVDD). Therefore, specialized therapeutic applications to induce intervertebral disc (IVD) regeneration is a necessity. Here, we report the use of a collagen-mimetic bioactive peptide nanofiber scaffold (Col-PA/E-PA) for the improvement of disc regeneration by recapitulating the structure and function of the natural extracellular matrix (ECM) of intervertebral connective tissue. Following two weeks of degeneration, the bioactive nanofiber scaffold was topically applied and the IVD regeneration process was observed through histochemical analyses. The collagen-mimetic bioactive peptide nanofiber system was found to significantly promote glycosaminoglycan and collagen deposition at the site of injury compared to control nanofiber system and saline groups. In addition, the bioactive scaffold was consistently associated with lower values in degeneration scoring analyses, confirming the functional recovery of the tissue. Overall, the collagen-mimetic peptide nanofiber scaffold was able to prevent the progression of IVD degeneration and provide further functional recovery to the tissue.