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SOX2 odak noktasında: SOX2 gen kopya sayısı varyosyonunun TCGA pancancer kümelerinde TP53 mutasyonu ile ilişkisi ve shiny uygulaması kullanılarak de novo SOX2 sentezi için kodon optimize tasarım
Recombinant proteins are crucial for diverse research applications such as biosensors and cancer studies. Proteins are engineered through de novo gene synthesis methods. Numerous tools and databases have emerged to facilitate the design of recombinant proteins, starting from the design of the gene sequence. De novo DNA synthesis enables the synthesis of custom-designed sequences, allowing codon optimization to enhance expression yield in heterologous systems. In cancer research, recombinant expression of proteins involved in tumorigenesis-related signaling pathways is employed for functional studies, potentially revealing new therapeutic targets. A notable example is the pivotal role of SOX2 expression in the formation of cancer stem cells (CSCs) across various cancer types. Previous studies highlight SOX2 expression functionally overlaps with TP53 expression on the PI3K/AKT signaling pathway. This association may stem from the p53-MDM2 interaction. This thesis investigates the association between SOX2 copy number gain and TP53 mutations within TCGA PanCancer cohorts. Fisher's exact test results reveal varying association, dependent on tissue type and specific driver mutations within each cancer type. The findings suggest the potential therapeutic relevance of SOX2 in cancer research. Furthermore, the thesis employs an in-silico approach to design de novo SOX2 synthesis, utilizing a novel shiny app that integrates codon optimization and primer design functionalities. The app enables simultaneous codon optimization for multiple expression systems and offers distance analysis through hierarchical clustering. Codon optimization feature provides control over the rate of replacement value for codon substitution which validated through a case study involving human insulin. Finally, app design set of overlapping primers with synchronized melting temperature to be used in PCR assembly for de novo SOX2 gene synthesis. Keywords: Recombinant Protein, Cancer, TCGA-PANCAN, SOX2, TP53, Association Analysis, Codon Optimization, PCR Assembly, Primer Design
CAP-RNAseq: Gen esansiyelliğine ve mRNA ve protein düzeyleri arasindaki uyuma dayalı RNA-seq veri kümeleme, annotasyon ve önceliklendirme için çevrimiçi bir platform
In 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.
Yukarıdan aşağıya dikkat süreçlerinin eylem algısı ağı üzerinde etkisi
Action perception is one of the fundamental skills for survival and social interaction. In neuroscience literature, it is well-established that when an action is visually perceived, the Action Observation Network (AON) becomes active in the human brain. This network has three core brain regions: the posterior superior temporal sulcus (pSTS), parietal cortex, and premotor cortex. Recent studies in neuroscience have shown that action perception is not a passive process but is affected by top-down signals such as attention. In this study, we investigated the influence of attention on the AON by conducting a two-session fMRI experiment. The stimuli comprised eight videos of pushing actions, with each video featuring a unique combination of actor (female or male), effector (hand or foot), and target (object or human). In the active fMRI session, participants viewed the videos while performing three different tasks that directed their attention to distinct features of the action (actor, effector, target). In the passive fMRI session, participants viewed the same videos without performing any task. The data from the passive session was used to extract ROIs: pSTS, parietal, and premotor in each hemisphere. Univariate analysis, representational similarity analysis (RSA), and decoding analysis were performed. Univariate analysis showed that introducing attentional demands during video viewing elicited a significant increase in neural activity within both parietal and premotor cortices relative to passive viewing conditions. RSA results revealed significant correlations between neural activity patterns and task models across all ROIs, indicating top-down influence throughout the AON. Decoding analysis showed unique top-down effects in each ROI, depending on its hierarchical level and intrinsic selectivity. These findings demonstrate strong top-down modulation of the AON based on cognitive demands, highlighting the dynamic interplay of attention and action perception.
Farkli alt görevlerle ilişkili çalişma belleği ayri, müdahale etmeyen depolarda korunabilir
How can WM maintain more information when its capacity is only around 4 items? Here, we explore the possibility that information related to separate subtasks do not count towards this limit, perhaps, because they are maintained in non-interfering stores. Across the two experiments, we investigated if increasing the WM load related to one subtask interfered with the execution of a concurrent but distinct second subtask. In Experiment 1, participants first saw pictures that were to be kept in mind and used for a later subtask B. They then executed subtask A, while keeping in mind these subtask B pictures. Although subtasks A and B involved maintaining and updating identical sets of pictures, increasing the number of subtask B pictures did not interfere with subtask A execution, which was only affected when the number of pictures relevant to it was increased, suggesting that subtask A and B pictures were maintained in separate non-interfering stores. An objection might be that in Experiment 1, subtask B pictures were passively and not goal-directedly maintained. In Experiment 2, participants executed a more complex subtask that forced participants to maintain and update two separate sets of subtask B pictures while executing subtask A and subtask A also involved WM maintenance and updating of identical pictures. We found that even here increased load of subtask B pictures did not affect subtask A performance. Thus, at least in some multitasking situations, information related to distinct subtasks can be maintained in separate non-interfering stores.
Fare serebral korteksinde hiperlipidemi kaynaklı organel stresini ve nöroinflamasyonunun incelenmesi: Perk yolağına müdahaleye ilişkin anlayışlar
Deficits in the metabolism of lipids called hyperlipidemia have been linked to a higher risk of developing neurodegenerative diseases. Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) signaling is crucial in cellular homeostasis. Abnormalities in the PERK have been associated with neurodegeneration. Mitophagy and the PERK pathway emphasize how cellular stress responses are regulated to preserve cellular homeostasis and mitochondrial quality control. The activity of main mitophagy regulators, such as Parkin and PINK1 (PTEN-induced kinase 1), is regulated by the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) by PERK. If lipid metabolism is at a high level, abnormalities in the mitochondria and endoplasmic stress (ER) emerge. During the ER stress activation, the PERK pathway is induced, and mitophagy is blocked, causing an enhancement in the neuroinflammation. The underlying molecular mechanism by which hyperlipidemia impacts the PERK pathway and mitophagy in the cerebral cortex, as well as the relationship between mitophagy and neuroinflammation, is not fully understood. In this study, Apoe-/- and C57BL/6 mice were given a chow or western diet to stimulate hyperlipidemia. Moreover, western diet-fed Apoe-/- mice were injected with PERK inhibitors, GSK2606414 and Trans-ISRIB, intraperitoneally for six weeks to suppress the PERK pathway. This study explores the effects of hyperlipidemia on the PERK pathway, inflammatory and mitophagy markers in the cerebral cortex of chow and western diet-fed C57BL/6 and Apoe-/- mice and investigates whether the inhibition of the PERK pathway can change the levels of inflammatory and mitochondrial markers in the cerebral cortex of hyperlipidemic mice subjects. mRNA and protein expression levels of mitophagy and inflammatory markers were assessed using the RT-qPCR and western blot, respectively. PERK pathway activation under hyperlipidemia conditions was not determined. Nevertheless, significant alterations in mitophagy markers and inflammation were detected in Apoe-/- mice apart from the diet. Furthermore, significant alterations were not seen in the PERK pathway markers; however, mitophagy was stimulated, and some inflammation markers were significantly decreased mildly at the cortical tissue of WD-fed Apoe-/- mice administrated with PERK pathway inhibitors, GSK2606414 and Trans-ISRIB. Besides, no statistically significant changes were observed in the transcript levels of the inflammatory markers. Taken together, hyperlipidemia did not cause the PERK pathway to be activated in the cerebral cortex of mice; nevertheless, it mildly altered inflammation and caused mild effects of the dysregulation of the mitochondria by hyperlipidemia independent from the PERK pathway. Furthermore, although the PERK pathway was not inhibited by the administration of PERK pathway inhibitors, mitophagy was induced, and inflammation was decreased mildly. Targeting the PERK pathway with GSK2606414 and Trans-ISRIB inhibitors from the cerebral cortex would not be a therapeutic approach for neurodegenerative diseases.
Yüksek yağlı diyet ile genotipin farenin serebral korteksinde kan-beyin bariyeri ve sinaptik bütünlüğe etkileri: PERK yolağının araştırılması
High-fat diet intake can induce hyperlipidemia and result in cognitive decline by causing endoplasmic reticulum stress, decreased blood-brain barrier, and synaptic integrity. The protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is one of the arms of the unfolded protein response, which is activated by endoplasmic reticulum stress. The PERK inhibits the global protein translation while allowing the translation of certain proteins that are involved in inflammation and apoptosis. Due to its apoptotic properties, it is thought that the PERK pathway causes neurodegeneration. To study the effects of hyperlipidemia, a high-fat diet-fed Apoe knock-out mice model (Apoe-/-) is appropriate. Knocking out the Apoe in mice makes the animal model more prone to high-fat diet-induced hyperlipidemia. In the cerebral cortex of these animals, endoplasmic reticulum stress, blood-brain barrier, and synaptic integrity markers are checked at protein and mRNA levels. No changes are observed in the PERK pathway markers besides phosphorylated eukaryotic Initiation Factor 2a. Additionally, there is a significant increase in blood-brain barrier marker Claudin-5 levels in Apoe-/- mice fed with a high-fat diet. There is also no significant change in synaptic integrity markers. In the second part, the effects of the PERK pathway inhibition are checked with integrated stress response inhibitor and GSK2606414 in the high-fat diet-fed Apoe-/- mice cerebral cortex. There are no significant alterations in BBB and synaptic integrity when the animals are injected with inhibitors. In conclusion, this study investigates the effects of high-fat diet induced hyperlipidemia in the cerebral cortex of Apoe-/- mice on ER stress, blood-brain barrier, and synaptic integrity. In the cerebral cortex region, the PERK pathway-related ER stress is not observed, and synaptic integrity remained unchanged while the blood-brain barrier is affected. Moreover, the effects of the PERK pathway inhibition are researched, and there is no inhibition effect observed in the cerebral cortex region.
Dss kaynakli er stresin ire1 ve jnk sinyal yolaklarinin fare serebral korteksinde incelenmesi̇
Endoplasmic reticulum (ER) stress plays a critical role in cellular homeostasis and is implicated in various neurodegenerative diseases. The inositol-requiring enzyme 1 (IRE1) is one of the arms of the unfolded protein response (UPR), which is activated in the presence of ER stress. IRE1 pathway activates c-Jun Nterminal kinase (JNK) downstream under prolonged stress. This thesis explores the activation of the IRE1 and JNK signaling pathways in the mouse cerebral cortex following DSS-induced colitis, focusing on their roles as markers of ER stress in the context of the gut-brain axis. While DSS-induced intestinal inflammation and ER stress are well-established, neurological effects remain less understood. Employing a murine model, the study explored ER stress markers in the cerebral cortex resulting from intestinal pathology. Despite evidence of DSS-triggered systemic inflammation and ER stress in intestinal tissues, our study revealed no significant differences in the expression levels of IRE1, p-IRE1, or the p-IRE1/IRE1, nor in JNK, p-JNK, or the p-JNK/JNK between the control and DSS-treated groups. Additionally, these results are supported with correlational and linear discriminant analyses (LDA). These findings suggest that acute DSS-induced colitis did not elicit a detectable ER stress response in the mouse cerebral cortex under the conditions used. Possible explanations include tissue-specific reactions to the ER stress, transient activation of the IRE1-JNK pathway that returned to baseline by the time of analysis, or potential survivor's bias. Despite its limitations, this thesis provides a novel investigation into the effects of DSS-induced colitis on ER stress in the cerebral cortex.
Çeşitli uzatılmış bilişsel görevlerde psikofizyolojik ve FMRI tepkileri: Başlangıçtaki ve sürekli aktivitenin karşılaştırılması
Bu doktora tezi, bilişsel yükün karmaşık dinamiklerini, özellikle ön-paryetal çoklu talep (MD) bölgeleri ve varsayılan mod ağına (DMN) odaklanarak, nöral ve psikofizyolojik temellerini incelemektedir. Çizgi yönelimi, dokunsal karar verme ve işitsel n-back görevlerini kapsayan bir dizi deney aracılığıyla, görev başlangıcı ve yürütme sırasında ortaya çıkan farklı aktivasyon örüntüleri araştırılmaktadır. Özellikle göz bebeği genişlemesi gibi psikofizyolojik tepkilerle nöral aktivasyon arasındaki ince ilişkiyi ele alan çalışma, bilişsel yükün çok yönlü ve duruma bağlı tezahürlerini ortaya koymaktadır. Bulgular, bilişsel yükün tekil bir yapı olduğu görüşüne meydan okumakta ve bunun birden fazla, bağlama özgü nöral mekanizmayı harekete geçirdiğini göstermektedir. MD bölgelerinde gözlemlenen doğrusal olmayan aktivasyon örüntüleri, görev başlangıcı ile sürdürülen katılım sırasında farklı roller üstlendiğini ortaya koyarken, DMN'nin özellikle erken görev aşamalarında MD bölgeleriyle örtüşen işlevler sergilediği görülmüştür. İki taraflı temporoparietal bağlantı bölgeleri (TPJ), bu ağlar arasındaki geleneksel sınırları aşan önemli bir düğüm olarak öne çıkmaktadır. Ayrıca, göz bebeği genişlemesi bu nöral dinamikleri yansıtarak, bilişsel yükün güçlü ve invaziv olmayan bir göstergesi olarak potansiyelini ortaya koymaktadır. Araştırma, farklı görev talepleri boyunca bilişsel kaynakların dinamik olarak nasıl tahsis edildiğine dair daha derin bir anlayışa katkıda bulunmaktadır. MD ve DMN bölgeleri arasındaki etkileşime dair kanıtlar, bilişsel kontrol ve öz referanslı işleme için entegre bir çerçeve önermekte ve teorik çıkarımların ötesine geçerek klinik, eğitim ve insan-bilgisayar etkileşimi alanlarında uygulama olanakları sunmaktadır. Bu, nöropsikiyatrik bozuklukların teşhis ve tedavisinde ilerlemeler, bilişsel eğitim programlarının optimize edilmesi ve teknolojik arayüzlerin geliştirilmesi gibi potansiyel kazanımları içermektedir. Nörogörüntüleme, psikofizyolojik ve davranışsal paradigmaları bir araya getiren bu tez, bilişsel yükü yöneten nöral mekanizmalar hakkında kapsamlı bir açıklama sunmaktadır. Beyin ağlarının karmaşık dinamiklerini anlamamızı ilerleterek, çeşitli bağlamlarda bilişsel taleplerin değerlendirilmesi ve yönetimi için yenilikçi yaklaşımlar geliştirmek adına bir temel sunmaktadır. Anahtar sözcükler. Bilimsel Yük, Göz Bebeği Çapı, fMRI, BOLD Tepkisi, Galama
Algısal karar verme süreçlerinin altında yatan nöral dinamikler: Biyolojik hareket yön ayrımı deneyiyle bir EEG çalışması
Algısal kararlar çevreyle olan etkileşimlerimizin temelinde yer alır. Bu karar süreçleri, temel varsayımı gürültülü duyusal kanıtın belirli seviyeye kadar biriktirilmesi olan modeller aracılığıyla incelenmektedir. Algısal kararların altında yatan dinamikler insanlarda da EEG aracılığıyla gözlemlenmiş ve bu olaya ilişkin potansiyel centro-parietal pozitiflik (CPP) olarak isimlendirilmiştir. Bu varsayımlar ve CPP çeşitli deneylerle doğrulansa da biyolojik hareket algısı bağlamında henüz geniş kapsamlı incelenmemiştir. Bu çalışmada, ekranda süregelen bir görsel uyaranın olduğu ve hedef uyaranlara kesintisiz bir şekilde geçiş yapıldığı bir tasarım kullanılmıştır. Bu deney dizaynı, yaygın olarak kullanılan rastgele nokta hareketi deneylerinden esinlenilmiştir. Bu bağlamda, karıştırılmış hareketi takip eden nokta-ışık uyaran şeklinde insan hareketi gösterimleri kullanılmıştır. Katılımcıların iki alternatifli zorunlu seçim görevinde yürüme yönünü tayin etmeleri beklenmiştir. CPP'nin kanıt birikiminden ortaya çıkan karar değişkenini yansıttığı, duyusal kanıtın gücüyle ölçeklenen bir artış oranı ve karar bildirme zamanına yakın bir ortak genlik seviyesine ulaşmasıyla gösterilmiştir. Ek olarak, CPP deney içerisindeki doğru ve geçersiz cevaplar arasında ayrım göstermiş, karar süresini tahmin edebilmiş ve difüzyon-sürüklenme modeli çıktılarından sürüklenme oranı parametresiyle pozitif yönde ilişkilendirilmiştir. Ayrıca, hedef uyaran öncesi dikkat seviyeleri ve biyolojik hareket algısına özgü sinyaller incelenmiştir. Hedef öncesi dikkatin, takip eden gelişmiş görsel işleme arabulucuğuyla karar verme süreci üzerindeki etkisi görülmüştür. Sonuç olarak, çalışmamız CPP hakkındaki önceki bulguları biyolojik hareket literatürüne genişletmiş ve algısal kararların altında yatan farklı dinamikleri ortaya çıkarmıştır.
Sacsin'in glial ara filament organizasyonu ve inflamatuar sinyal yolağındaki rolünün erken dönem zebrafish gelişiminde araştırılması
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by early-onset ataxia, spasticity, and peripheral neuropathy. While ARSACS has been primarily studied in neurons, recent findings implicate glial cells in disease pathology. Sacsin, the protein encoded by the SACS gene and mutated in ARSACS, is shown to be expressed in both astrocytes and microglia while playing key roles in cytoskeletal integrity and cellular stress signaling. When adding the growing recognition of ARSACS as a disorder with neurodevelopmental components, investigating glial contributions to the disease pathogenesis during early development is becoming a requirement. This study aimed to investigate the impact of sacsin deletion on developmental and glial markers in zebrafish embryos and larvae, using a sacs-null mutant model of ARSACS. To this end, we quantified gene and protein expression profiles of sacsin and key glial markers across developmental time points (60–180 hours post-fertilization, hpf). RT-qPCR was used to assess the expression of sacs, s100b (astrocytic inflammatory marker), and aif1l (microglial inflammatory marker IBA-1), while Western blotting was used to examine protein levels of STAT3 (developmental marker), vimentin (early glial intermediate filament marker), and GFAP (astrocytic intermediate filament marker). Zebrafish sacs-null mutants showed a significant decrease in sacs mRNA expression only at 180 hpf, while the lack of earlier differences is possibly due to the stable mutant transcripts. Among glial inflammatory markers, s100b expression was significantly upregulated in sacs-null mutants; however, aif1l showed no genotype-dependent changes, reflecting a compensatory response of astrocytes that may even occur earlier than the microglial response. Additionally, no significant correlations were found between sacs and these glial inflammatory markers, indicating selective, possibly indirect, molecular interactions. Vimentin protein expression was significantly higher in sacs-null mutants, supporting the notion that sacsin loss disrupts intermediate filament dynamics, not just structurally, but in quantity. However, GFAP expression did not differ between genotypes, unlike the literature based on cellular imaging, suggesting the necessity of anatomical tissue-specific assays. Together, these results demonstrate that sacsin loss leads to selective and temporally defined alterations in glial development, particularly affecting cytoskeletal and inflammatory markers. The zebrafish model effectively captured these dynamics, validating its utility for studying glial contributions to early-onset neurodegenerative diseases. In conclusion, this study advances our understanding of glial dysregulation in ARSACS and underscores the importance of considering non-neuronal mechanisms in early disease progression. In future studies, tissue-specific analyses based on the imaging of glial cells in the central nervous system will be of critical importance for uncovering the molecular foundations of glial involvement in ARSACS and related disorders.
Çoklu görev sırasında farklı görevlerin çalışan bellek yükünün etkileri farklılaşabilir: Bir fMRG çalışması
Multiple demand (MD) regions are well-known for their activation pattern in task-related events and are especially sensitive to working memory load (WM) conditions. Different WM loads deplete varying amounts of WM capacity and may lead to interference. However, whether MD regions are sensitive to precision in addition to cognitive load still remains unclear. This thesis investigates whether challenging multitasking induces interference and whether brain responses to demanding tasks are modulated by precision. Thirty healthy participants (M = 27.1) underwent two fMRI runs and completed a hierarchically nested visual WM task, where task A's items were maintained during task B under alternating high and low WM loads. Parametric modulation, whole-brain, and region-of-interest (ROI) analyses were performed. Results showed that MD regions were activated during the encoding phase of task B, whereas task A exhibited a deactivation pattern. However, tasks were not differentiated during their corresponding retrieval steps. Brain regions correlating with performance accuracy also did not differ. The Default Mode Network (DMN) showed sustained deactivation during recall, regardless of task type, indicating domain-general suppression mechanisms. These findings support hybrid WM models that allow flexible control mechanisms and discrete capacity limits. The MD network appears to adjust engagement depending on task context and phase, aligning with hierarchical models. Task-specific encoding but shared recall dynamics suggest that while storage may be selectively distributed, retrieval relies on generalized control. This enhances understanding of cognitive control–memory interactions and highlights the need to examine individual differences to inform interventions for WM-related disorders.
Ergen ve genç erişkin nüfusta çevresel risk faktörlerin çalışma belleği sırasındaki nöral aktivasyon ve dinlenim halindeki fonksiyonel bağlantı üzerindeki etkisi ile psikoz eğilimine ilişkin etkileri
Experiencing symptoms of psychosis, such as delusions and hallucinations, is sometimes observed in the general, nonclinical populations in a mild form, and is often termed psychosis proneness (PP), potentially as part of the psychosis continuum. Understanding the neural, environmental and cognitive factors contributing to PP in young individuals during critical developmental periods remains unclear. Environmental risk correlations, causal factors, and neural correlates of psychosis proneness were investigated using fMRI during both task performance and resting state. To this end, three different studies were conducted. The first study examined the relationship between environmental risk factors including ethnic minority or migration history, obstetric complications, paternal age, urbanicity, trauma, cannabis use, and psychosis proneness and schizotypy using multilevel mixed effects linear regression. Additionally, schemas about the self and others were used to predict psychosis proneness and schizotypy, alongside an exploration of its neural correlates during working memory performance. In the second study, we used a data-driven approach, causal discovery analysis (CDA), a novel machine learning algorithm, to explore directional relationships among variables. The analysis identified negative self-schema as having the largest causal effect on psychosis proneness among all assessments. Furthermore, experiencing low levels of social cohesion and trust had a causal effect on psychosis proneness. Although our analysis could not exclude the possibility that other unmeasured factors may confound these relationships, the effect sizes (ES) were substantial: negative self-schema & PPS (ES= 0.54) and social cohesion and trust & PPS (ES= -0.18). Moreover, PPS was identified as a direct cause of increased activation in the dorsolateral prefrontal cortex (DLPFC) during working memory (ES= 0.12). CDA provided simultaneous directionality for 37 variables measured in the same individuals. Finally, in the third study, we applied CDA to a dataset that included resting-state fMRI functional connectivity (FC) indices, with two different configurations of prior knowledge. Negative self-schema and social cohesion & trust again emerged as a direct causal factor for psychosis proneness. However, psychosis proneness did not appear to influence mean FC indices during rest. Instead, it directly affected individual FC indices within the dorsal attention network. These findings highlight the significance of negative self-schema and social cohesion and trust in the general population with psychosis proneness, suggesting potential preventive interventions targeting these factors. Furthermore, the results highlight the roles of the DLPFC during working memory and the dorsal attention network during rest as a potential targets for understanding and addressing psychosis proneness. These findings represent the first data-driven analysis modelling causal mechanisms underlying psychosis proneness in the general population and further support the hypothesis of continuum of psychosis.
Dikkatimizi ne çekiyor? Robot ve insan tarafından yapılan iletişim içeren ve içermeyen hareketlerin farklı algısal yük koşullarında görsel dikkat incelemesi
This study investigated how agent type (human vs. robot), communicativeness (communicative vs. non-communicative), and perceptual load (low vs. high) interactively influence visual attention and task performance. A 2 (Agent) × 2 (Communicativeness) × 2 (Perceptual Load) within-subjects design was employed with 34 participants. To examine attentional allocation under perceptual load, Areas of Interest (AOIs) were defined for the central letter array and the peripheral agent videos. Behavioral performance (reaction time, accuracy) and multiple eye-tracking metrics (total dwell time, dwell time per fixation, first fixation latency, saccadic velocity, pupil dilation) were analyzed. Behavioral results confirmed the effect of the perceptual load manipulation, with participants being significantly less accurate and slower in high-loaded conditions. In the presence of a distractor, reaction times and accuracy were further modulated by significant interactions between agent, perceptual load, and communicativeness. Eye-tracking analyses revealed that initial orienting was driven by the communicativeness and perceptual load, when communicative cues captured attention faster only under high load. Dwell time per fixation remained stable across the conditions. On the other hand, total dwell time revealed a critical three-way interaction. Under high load, communicative actions performed by humans increase total dwell time, whereas if the action is performed by a robot, dwell time decreases. Pupil data supported this, indicating that under high load, non-communicative actions required more cognitive effort than the communicative ones. Initial orienting of eye metrics was guided by task demand; overall engagement with the nature of the action is a product of a complex and sensitive cognitive process sensitive to perceptual load. Robotic social cues are processed dissimilar compared to human ones.
Motivasyonel koşulların zaman persepsiyonu üzerindeki etkisi bir tersine öğrenme paradigmasında
Time perception, a fundamental cognitive process, can be influenced by various external and internal factors such as adaptability, attentional control, and reinforcement learning. Understanding how motivation affects time perception is important in dynamic learning environments where participants must adapt to changing conditions and make timely decisions. To study the influence of food manipulation on participant's time perception, three experiments were designed in current study which involved reversal learning. Two food conditions; experimental and control. In one condition, a calorie-rich snack was provided at 10-minute intervals during breaks. No snack was offered in the control condition. The first experiment was conducted in a basketball court, where participants were rewarded by scoring the right basket. After a fixed interval, the basket changed, and scoring on the other side became correct. In the second experiment, there were two darts boards and participants threw darts at one of the two dartboards. After a fixed interval, the dartboard switched, and scoring on the other side became correct. In the third experiment, the task was to build houses of cards, with the correct table switching back and forth after a fixed interval. In all three experiments, participants were paid to score on the correct side. Our results suggest that food motivation influenced participant's time perception in the cards-based experiment but there was no effect of food manipulation on time perception of participant's in basketball and darts throwing experiment. Task difficulty affected time perception significantly and proficiency in the specific task being performed also affected time perception in all experiments. The interactions of food condition, proficiency and satiety was also checked which shows that even though food motivation was not significant in first two experiments, its interaction with other factors can be significant. This study extends the research on reversal learning and contributes to the understanding of various factors influencing human cognitive processes. It contributes to understanding how food manipulation interacts with adaptive decision-making and time perception under changing task requirements.
Düşüncenin bedensel haritaları: Düşünceler kafanın farklı bölgelerinde toplanır
The mind and body are tied together; research on embodied cognition shows that people feel the Self and emotions in the body. They are processed in the mind and perceived through the body template. Building on this notion, we asked whether thoughts are experienced in the body template similarly and whether different kinds of thoughts are located in different bodily regions. In a behavioral experiment, we gave participants short scenarios in five different categories and asked them to imagine/think about those scenarios. Then they were asked to locate their thoughts and images on head and full-body templates. We compared within-category distances to between-category distances, examined each category pair for distinctness, and checked whether any category stood out for being especially tight and consistent. Results showed that people do locate their thoughts on their body template, and different thoughts are located differently from each other. Specifically, thoughts on mental arithmetic and auditory imagery formed distinct groups on the head template compared to other categories. In a second behavioral experiment, we replicated the task with blind and deaf individuals and found that distinct mapping patterns for different thoughts exist in blind individuals, but not in deaf individuals. When compared to other categories, auditory thoughts in blind individuals revealed a very clear and distinct pattern, while visual imagery in deaf individuals showed a distinct localization that differed from other thoughts. Taken together, our findings show that thoughts are located in the body template, with different thoughts located distinctly from each other, and that these localizations are affected by visual and auditory loss.
Şizofreni genetik riskinin adolesan gelişimi boyunca üçlü ağ modeline haritalanması: Boylamsal bir çalışma
The Triple Network Model, which includes the Default Mode Network (DMN), Frontoparietal Network (FPN), and Salience Network (SN), is a core model for schizophrenia and explains all the positive, negative, and cognitive symptoms. Many studies demonstrated the importance of the Triple Network Model in schizophrenia; however, no longitudinal study has yet examined the between‑network connectivity among the three Triple Network systems in healthy adolescents. To address this gap, we conducted a one‑year investigation of between‑network functional connectivity during typical development and assessed how genetic liability to schizophrenia moderates these changes. In this thesis, 89 pairs of twins and siblings were recruited and underwent resting‑state fMRI at baseline and one‑year follow‑up, with ROI‑to‑ROI functional connectivity values computed separately for each session. Participants also completed the CAPE‑42 to assess subclinical psychotic symptoms and provided blood or saliva samples for genotyping to derive schizophrenia polygenic risk scores (PRS‑SCZ). Using linear mixed‑effects models, we evaluated (1) whether significant longitudinal connectivity changes occurred, (2) whether PRS‑SCZ moderated these longitudinal changes, and (3) whether connectivity changes were associated with subclinical psychotic symptom scores (total, positive, negative, and depressive). We found no significant time effect from baseline to follow‑up; however, PRS‑SCZ significantly moderated connectivity trajectories, with higher PRS‑SCZ associated with greater increases in FPN–SN, DMN–SN, and DMN–FPN connectivity. Specifically, PRS‑related enhancements were observed in the connections between left lateral prefrontal cortex (LPFC)–left supramarginal gyrus (SMG), left posterior parietal cortex (PPC)–right rostral prefrontal cortex (RPFC), right PPC–right SMG, left anterior insula (AI)–left lateral parietal cortex (LP), left PPC–left posterior cingultae cortex (PCC), and right PPC–right PCC. None of these PRS‑modulated connectivity changes, however, were significantly associated with changes in subclinical symptom scores. The PRS‑SCZ–related connectivity increases paralleled patterns observed in patients and other high‑risk groups, suggesting that these alterations may reflect early neurodevelopmental mechanisms underlying schizophrenia pathology before the emergence of clinical symptoms. These findings highlight the potential of Triple Network Model functional connectivity as an early biomarker of schizophrenia risk and underscore the need for extended longitudinal follow‑up to capture non‑linear developmental trajectories.
Eş seçimi bağlamında kıskançlık ve zihinselleştirmenin etkileşimi
Mate choice is a multifaceted decision mediated by mentalization and jeal- ousy, etc. Jealousy is conceptualized to alter attentional bias toward con- textual cues and recalibrate partners' valued traits. This thesis examined whether a jealousy induction, compared to a control group, alters perspec- tive taking, jealousy state, attentional bias, and preferred traits ranking. 48 participants completed: a dot-probe (image/words), MJS (Multidimensional Jealousy Scale), DMASC-MC (Double Movie for the Assessment of Social Cognition — Multiple Choice), a 12-item trait ranking, and the Draw E task. Drawing E was modeled using logistic regression. By filtering out in- valid/missing data, the analytic numbers were: MJS and trait-rating n=48 (Control=24, Experimental=24), DMASC-MC n=46 (Control=23, Experi- mental=23), and dot-probe n=45 (Control=21, Experimental=24). Results and discussion: for both Dot-Probe and DMASC-MC: baselines controlled, groups did not differ at post, rather pre-test covariations were highly predictive: Dot-probe: F (1,42) =0.21, p=.652; covariation F (1,42) =19.25, p<.001. Baseline total RTs were comparable (0.776 vs. 0.832 s); DMASC-MC: using ANCOVAs, (post Group + pre), no sig. between- groups posttest (Cognitive: F (1,43) = 0.05, p=.819; Count "N-Correct": F (1,43) = 0.56, p=.460); covariate F (1,43) = 20.97, p<.001). MJS: no discernible between group changes (Total t(46)=-1.05, p=.300, g=-0.30; Be- havioral t(46)=-0.28, p=.784, g=-0.08; Cognitive t (46) = -1.89, p=.065, g=-0.54; Emotional t(46)=-0.08, p=.939, g =-0.02; ). Trait-rating: Trait, Session, and Trait×Session, were significant (Trait: F (3.46,159.16) =155.59, p<.001, ω2≈.67; by Session (F (1,46) =145.94, p<.001, ω2≈.19); with change over Session varying by Trait (F (2.50,114.77) =162.81, p<.001, ω2≈.47)); Group showed no effects. Logistic regression: Age was a positive predictor of self-oriented E. Also, in our logistic modeling, the direction of writing, age, sex and their interaction improved the fitness of the prediction of self- oriented (∆χ2(4)=12.30, p=.015 (McFadden R2=.27; Nagelkerke R2≈.37; Tjur R2≈.33)). The priming manipulation did not yield condition-specific re- sults on the battery tests, suggesting more intense/prolonged manipulations. Nevertheless, the significant logistic results of age underpin a trajectory of intrapersonal differences in perspective-taking, offering further studies.
Yapılı çevrelerde huşu: Mimari stil ve bakış açısının görsel tanıma belleğine etkileri
In recent years, there has been a growing interest in neuroarchitecture. This emerging field integrates neuroscience, psychology, and architecture to investigate the built environment's impact on cognition, emotion, and behavior. Aesthetic and emotional responses to architecture, especially the experience of awe, are becoming more recognized as significant factors influencing cognitive processes, including attention, memory, and decision-making. However, the association between awe, components of architecture, and perceptual perspective is still insufficiently examined. The present study investigated the interactions among awe, architectural style, and viewing angle on visual recognition memory in built environments, employing a 2 (awe: awe-evoking vs. non-awe-evoking) × 2 (style: traditional vs. modern) × 2 (angle: eye-angle vs. low-angle) within-subjects design. Thirty-six participants participated in a visual recognition memory task involving real-life architectural imagery. Analyses of recognition sensitivity (d′) indicated that traditional architecture revealed higher recognition sensitivity than modern architecture, and eye-angle perspectives yielded better sensitivity than low-angle perspectives. Awe alone did not yield a significant main effect; however, it interacted with architectural style, diminishing discriminability for modern architecture while having no effect or a slight improvement on traditional architecture. Analyses of the response criterion (c) revealed that awe, style, and angle independently modulated decision thresholds, with awe‐evoking images eliciting a more liberal bias. This study contributes to the existing literature by establishing the contextual restrictions of awe's mnemonic effects, indicating that architectural stimuli's perceptual and stylistic characteristics moderate its influence on memory. The combination of affective science, neuroarchitecture, and signal detection theory provides a new framework for analyzing the interplay between aesthetic and perceptual factors in shaping memory within the built environment.
Ko-ekspresyon çiftleri ve modülleri (CoEX-PM): Bir Shiny aplikasyonu ve kromograninler üzerinde bir örnek olay incelemesi
Gene 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 the presence of concise and highly co-expressed functional components in PCC and NB driven by chromogranin expression signatures.
Psikoza yatkın bireylerde çalışma belleği aktivasyonunun aritmetik ve zamana bağlı dönüşümleri
Working memory (WM) de ficit 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 fi nding 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.
Kontrast ve büyüklüğün hareket algısındaki rolü: Kortikal bölge v1 ve MT'deki çevre ve merkez etkileşimlerinin fMRI ve davranışşal deneylerle incelenmesi
Behavioral experiments have demonstrated that observers' ability to discriminate the drift direction of a grating improves as its size increases if the grating has a low contrast, and deteriorates if it has a high contrast. It has been proposed that receptive field organization in middle temporal (MT+) visual area underlies this counter-intuitive perceptual effect. Supporting evidence for this proposal has been provided in literature. However, previous studies have not unequivocally showed that MT+ is the sole area whose activity underlies the perceptual effect. Here, we investigate the activity patterns of primary visual cortex (V1) and middle temporal (MT+) in response to drifting Gabor patches in differing size and contrast levels to elucidate the neural region involved in size-contrast interac- tion in motion perception. We first replicated the findings in the literature with a behavioral experiment, where small or large (1.67 and 8.05 degrees of visual angle) drifting gratings with either low (2%) or high (99%) contrast levels were presented at the periphery (centered 9.06 degrees of visual angle to left and right of fixation). We measured the duration thresholds (79%) for accurately discrim- inating the drift direction of gratings for eleven participants using an adaptive staircase and two-alternative forced choice (2AFC) design. In line with previous literature, we observed that increasing the size of the low-contrast stimuli resulted in decreased discrimination threshold, while for high-contrast stimuli, increasing the size resulted in increased discrimination threshold. In the second stage of the study, six observers participated in a block design fMRI study with the same spatial configuration and contrast levels used in the behavioral experiment. We first identified the region of interests (ROI) for visual area V1 and MT+ separately for all participants. Then, we identified a "sub-ROI" that corresponds to the region that was selectively responsive to the small sized stimuli (1.67 degrees) using an independent localizer. With this setup, we allowed for both large and small sized gratings to stimulate the sub-ROI throughout the entire scan. Therefore, changes in Blood Oxygenated Level Dependent (BOLD) response at the sub-ROI in response to large compared to small sized gratings indicated the influence of the surrounding region to the center of the gratings. In area MT+, we observed that increasing the size of the grating increases the BOLD activity if the stimuli have low contrast, compared to high contrast. In other words, surrounding region had a facilitative influence to the group of MT+ neurons encoding the center of the stimuli if the stimuli had low contrast. This neuronal facilitation observed with the neuroimaging data explain the enhance- ment of the performance with increasing the size of the low-contrasted stimuli observed at the behavioral experiment. In V1, however, increasing the size of the high-contrasted gratings increased the BOLD activity, compared to activity evoked by increasing the size of the low-contrasted gratings. On the whole, we show that center-surround interaction in V1 and MT were differentiated in re- sponse to peripherally viewed drifting Gabor patches at differing contrast and size levels, hence we provide further evidence that the perceptual size-contrast interaction effect is likely to originates at cortical area MT+.
Sağlıkla ilgili bilgiler üzerine yorumlama ve dikkat yanlılıklarının karşılıklı etkileri
tive processing biases to health-related information have been endorsed to be present in patients who are suffering from medical diseases. Attentional bias is one of the cognitive processes which facilitates the detection of health-threatening information. Interpretation bias is the other cognitive mechanism that makes patients attribute catastrophic meanings to ambiguous bodily sensations. Despite the literature demonstrating that attentional and interpretation biases increase negative emotions and challenge patients for adaptation to their health condition, the link between these two biases has remained unclear. While some theories claim that attentional and interpretation biases are interrelated, some state that they might be orthogonal components of cognitive processing. Therefore, this thesis aimed to investigate the relationship between interpretation and attentional biases to health-related information by modifying interpretation bias and studying its effect on attentional bias. One hundred undergraduate students who lack any medical or psychological problems were randomly allocated to Main-Modification or Placebo-Modification groups. All participants were asked to complete a battery of questionnaire including health anxiety inventory, Beck depression inventory, and Beck anxiety inventory in order to control between-group differences regarding these constructs. As the pre-modification assessment, participants' interpretation and attentional biases to health-related information were respectively measured using the Modified Version of Online Interpretation Bias and Dot-probe tasks. Then, the Main-Modification group underwent Main On-line Negative Interpretation Bias Modification Task aimed to impose unsafe and threatening interpretations for ambiguous health-related scenarios. the Placebo-modification group completed Placebo On-line Negative Interpretation Bias Modification Task. The modification phase was followed by post-modification measurements. Results revealed that the participants in the Main-Modification group experienced more post-test interpretation bias indexed by Unsafe valence of interpretations for ambiguous health-related situations compared to the Placebo group. The Post-test between-group difference, however, was not significant for interpretation bias indexed by reaction time. Main negative interpretation bias modification succeeded to amplify attentional bias toward Ambiguous images in the Main group but Placebo modification did not do so. Unlike Placebo modification, Main modification increased attentional bias to Health-Related images as well. However, this increase was not statistically significant. These results can be considered as the pieces of evidence endorsing the idea that interpretation and attentional biases are interrelated aspects of cognitive processing. Repeated exposure to negative interpretations for health-related situations might increase patients' accessibility to negative meanings for interpreting further ambiguous health-related situations. In turn, the new negative meanings might facilitate detection of ambiguous bodily sensations or another health-related information known as attentional bias
Hareket algısındaki görsel-işitsel çağrışımların EEG korelatları
The process of associative learning has been considered to be one of the promising research areas in neuroscience to understand human perception, sensory plasticity, and multisensory integration that affects the way of perceiving external environment. Evidence suggests that associative learning causes unexpected lowlevel sensory plasticity in brain. Yet, how this effect occurs in low-level visual motion areas remains unclear. In order to examine the effect of audiovisual associations on visual motion perception, we conducted an experiment in which subjects are exposed to pre association test, associative learning and post association test phases. Moreover, EEG was recorded simultaneously to investigate neural mechanisms behind this effect. In associative learning task, a particular sound (low-frequency or high-frequency) was accompanied with a specific direction of random dot motion (leftward or rightward), and participants were asked to attend both sound and direction. Pre- and post-association tasks in which auditory-only, visual-only, audiovisual trials were presented are identical. During these trials, participants were asked to decide the direction of moving dots with a keypress except in auditory-only trials. We hypothesized that there will be significant differences in responses between pre- and post-association phases in accord with associative pairings that were given in associative learning phase. T-test results validated our hypothesis with a significance level at 0.01 (p-value = 0.008). In terms of neural mechanisms behind this effect, we also hypothesized that this effect originates from feedback mechanisms. ERP results indicated that associative learning influences early temporal processes (100-150 ms) to auditory only condition, and interaction effect occurs late in time after stimulus onset (around 500 ms). In this context, ERP results supports the hypothesis by revealing that modulation in early temporal areas transmits information to high level association areas that project information to low level visual areas, thus high latency is observed after stimulus onset.
Rovıngin algısal performans üzerindeki etkilerine görev zorluğu ve uzmanlık dahil olur
Experience-dependent improvement of perception, known as perceptual learning, is possible in the absence of feedback, but feedback enables faster progress as demonstrated by both unsupervised and supervised learning mechanisms. Perceptual learning models have shown that mixing these two learning mechanisms may potentially cause synaptic drift and disruption of learning. Models predict this disruption in simultaneously learning two tasks with differing difficulty levels, but not for tasks of equal difficulty. The roving, randomly intermingling of two different tasks, has thus sometimes been found to disrupt learning, but not always. Interestingly, the deleterious effect of roving may occur not only during learning but also even after a task has been learned. In this study, we examine roving's effects based on task difficulty as a function of expertise level. Subjects were trained with a vertical line bisection task, where they were asked to decide if the central line was offset to the left or right outer lines. Following training, the trained stimulus was roved with a narrower untrained bisection stimulus; half of the subjects were exposed to the roved stimuli, which were equated for difficulty using an adaptive staircase method, while other half were exposed to stimuli made to differ in difficulty levels using different staircase procedures for each. We demonstrated that performances improved with training. Moreover, roving deteriorated performance for the trained task under mixed difficulty conditions but not under matched difficulty conditions. Training participants over multiple days further revealed that roving's deleterious effects decreased with increasing expertise levels.
FMRG kan oksijen seviyesine bağımlı (bold) sinyalin insan birincil görme korteksinde zamansal ve konumsal nonlineerlikleri
It is generally assumed that fMRI BOLD response (i.e., functional magnetic resonance imaging blood-oxygen-level-dependent signal) is linear and time-invariant. In this study, we investigated spatial and temporal nonlinearities in fMRI BOLD response at different flickering durations (nearly instantaneous and 1 s). We presented participants two successive flickering checkerboard wedge stimuli with stimulus onset asynchrony (SOA) of 0 s, 0.5 s, 1.5 s, and 6 s. The spatial locations of the stimuli were categorized as the same location in the same hemifield, adjacent locations in the same hemifield, and between hemifields. We demonstrated that fMRI BOLD response behaves nonlinearly when the successive stimuli spatially and temporally were close to each other for both flickering durations. Nonlinearity between the successive stimuli was the highest for the same location in the same hemifield, higher in adjacent locations in the same hemifield, and the lowest in between hemifields. In addition, nonlinearity at the shorter SOAs (0 s, 0.5 s, and 1.5 s) was found to be higher than nonlinearity at SOA 6.
Popülasyon alıcı bölgeler modeli ile görsel korteks haritalandırılması: İMRG ve uyaran parametrelerinin ayarlanması ve alıcı bölge büyüklüğü incelemeleri
Human visual cortex has been studied extensively since blood oxygen-level dependent (BOLD) signal was discovered by magnetic resonance imaging (MRI) researchers in 1990's (Ogawa et al., 1990). It was not long after that, the researchers achieved to map human visual cortex with functional MRI (Sereno et al., 1995; Deyoe et al., 1996; Engel et al., 1997). In recent past, population receptive field (pRF) method was proposed by Dumoulin and Wandell for receptive field mapping (Dumoulin et al., 2008). Compared to phase-encoded methods, their model added a size parameter to receptive fields, referring to the extent of visual field region processed by neuronal populations. fMRI sequences from Human Connectome Project (Moeller et al., 2018) that used accelerated imaging to scan the whole brain of subjects at ultra-high resolutions were adapted to conduct retinotopy experiments in our institute, National Magnetic Resonance Center, Ankara. pRF maps estimated with three types of stimuli were compared. A local pRF estimation method was tested for a specific region on visual field to achieve greater detail in pRF maps. Subject specific hemodynamic response function (HRF) was estimated in a separate experiment to enhance the pRF estimation analysis. Moreover, pRF size differences were compared between stimuli, hemispheres, and visual processing streams. The results implied that stimulation by natural images yields reliable maps in higher level visual regions, and therefore was selected as the best stimulation protocol. In addition, a guideline has been prepared for vision researchers to conduct pRF analysis.
Korku duygusu içeren görsel uyaranların popülasyon alıcı alan tahminleri üzerindeki etkisi
Previous studies showed that the content of stimulus might affect the results of population receptive field (pRF) estimation method [1, 2, 3]. In addition, emotion might modulate visual processing in humans by increasing BOLD activity [4, 5]. Taken together, the stimulus with emotional cue might affect the pRF parameters. To investigate the effect of emotion on visual processing, we used the population receptive field (pRF) method [6], with simultaneous wedge and ring stimuli rendered with scrambled, neutral or emotional images. Results showed that the pRF estimations were affected by the stimulus content in visual areas hV4 and V3A, as well as lower retinotopic regions: V1, V2 and V3. Moreover, we showed the emotional content of stimulus might lead to the increased pRF sizes as well as a shift in pRF centers toward the eccentric side. We argue that the increased pRF size and the pRF shift might be a result of emotional modulation of visual processing.
İnsanların performansını karşılaştırmak ve 3D-konvoleksiyonel nöral ağlarda dinamik pişirme kullanılan malzeme anlayışı
There 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.
Zebrabalığı (Danıo rerio) modelinde yetişkin nörogenezi ve astositlerin yaşlanmaya bağlı değişimleri
Brain 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.
Zebrabalığı dokularında ve insan beyin kanserlerinde telomerlerin sürdürülme mekanizmalarının incelenmesi
Telomeres are nucleoprotein complexes formed at each end of the chromosomes to protect these ends from deterioration. In each round of cellular division, telomeric sequences shorten due to the end replication problem of DNA polymerase. Progressive telomere shortening results in replicative senescence in healthy somatic cells. To evade replicative senescence, cells need to maintain their telomere length either by activating the telomerase enzyme or through the alternative lengthening of telomeres (ALT). Telomerase is a holoenzyme, which is composed of dyskerin, telomerase RNA subunit (TR or TERC), and telomerase catalytic subunit (TERT). Dyskerin and TR are constitutively expressed in all cells but TERT expression is silenced in adult somatic cells. Thus, telomerase activity is dependent on the expression of TERT. Current studies show that TERT re-activation is a common feature of cancer cells and 85-90% of cancers utilize telomerase enzyme in maintaining telomeres to become immortal. Remaining of cancer cells maintain their telomeres by the alternative lengthening of telomeres (ALT), which is a DNA repair pathway dependent mechanism. Current models suggest that ALT is achieved by homology-directed DNA repair, through the interaction of multiple proteins. DNA methylation is regarded as a key player in epigenetic silencing of transcription. DNA methyltransferase inhibitors are currently being used in cancer treatments. Recent studies show that DNA methyltransferases and their expression levels impact both telomerase- and ALT mediated lengthening of telomeres, and have different outcomes in different tissue types. In this study, we worked on the zebrafish brain and human brain cancer cell lines. In zebrafish brain, we observed differences in methylated regions at Sp1 binding site between young and old that can be associated with telomere shortening. By silencing DNMT1 and DNMT3B in brain cancer cell lines, we investigated the changes in gene expression levels of telomerase and ALT related genes, telomerase activity, population doubling time and replicative senescence status. To further investigate TERT regulation, we introduced mutations to the Sp1 binding sites in the promoter region and measured the promoter activity with luciferase assay. Our results show that Sp1 methylation sites in the telomerase promoter region are critical in brain aging, dependent on their position. We propose a therapeutical option for brain aging and tumorigenesis.
Görsel algısal öğrenme sürecinde insan korteksindeki fonksiyonel değişimler
In this study we assessed functional changes through visual perceptual learning with bisection discrimination task. Before learning, after third session of learning and after learning ended, behavioral threshold and fMRI data has been collected. Our results showed that while participants showed threshold decrease in the mid-learning session, the post-learning thresholds are turned to pre-learning levels. These results might be due to fatigue which caused by our experiment. Besides to training condition, we also tested location and task specificity. The results showed that only 150\degree polar angle location showed significant change between sessions. Along with the behavioral data, we collected task-based fMRI data while participants performing training and control conditions in the scanner. The analysis showed task-based BOLD response changed with session. However, post-hoc tests did not reveal significant results. The resting-state functional connectivity analysis showed that the functional connectivity between V1 and V2 regions is significantly increased. The Post Hoc analysis showed significant change in the 210 degree and 150 degree polar angle conditions. The changes in the behavioral and functional connectivity measurements at 150 degree polar angle conditions, these results might indicate the effect of the inter-hemispheric connections. Moreover, our analysis on resting state data also revealed that, while there is no change between pre-learning and mid-learning sessions, connectivity changes significantly in the post-learning session compared to other sessions. This finding supports the idea that functional connectivity changes related to perceptual learning might be occurring at the late phases of the learning. Overall, to rule out the confounds in the behavioral measurements and to link the behavioral data with the neural data, additional measurements should be taken in the future.
Kısa süreli aralı oruç ve rapamisin uygulamalarının zebra balığı (danio rerio) beynindeki yaşa bağlı etkileri
World 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.
Probing sensory plasticity with rapid forms of motion adaptation
Perception is shaped by both immediate pattern of sensory inputs and previous experience with the external environment. Visual adaptation, a temporary change in perception following exposure to a stimulus, has been widely employed to understand how previous sensory experience on different timescales shapes perception. Visual motion adaptation is a powerful investigative tool to understand sensory plasticity and neural adaptation. However, the neural mechanisms underlying adaptation induced changes by visual motion are still subject to debate. In the present thesis, spatiotemporal dynamics, neural substrates, and the functional role of sensory plasticity in the human visual system were examined using rapid forms of motion adaptation paradigm combined with EEG. Specifically, how motion adaption-induced short-term sensory plasticity is reflected at the neural level and parallel with perceptual performance were explored. Participants were adapted to directional drifting gratings for either short (640 ms in Experiment 1; 188 ms in Experiments 2 and 3) or long (6.4 s in Experiment 1; 752 ms in Experiments 2 and 3) durations and used a counter-phase flickering (with constant polarity in experiments 1 and 2; polarity inverting within every step in Experiment 3) grating as a test pattern. Sinusoidal gratings of phi motion were employed in Experiment 1 whereas; square-wave gratings were used for phi and reverse-phi adaptations in experiments 2 and 3 to examine how ON and OFF pathways operate in the visual processing stream. Based on the EEG analyses in Experiment 1, the scalp sites relevant to motion adaptation were identified. Experiment 1 showed that both adapting durations led to significant motion aftereffects and EEG results showed that long adaptation produced stronger aftereffects than the short adaptation condition within 64-112 ms time range over occipital and parieto-occipital sites. Taken together, these findings provide important electrophysiological evidence that motion aftereffects reflect changes in cortical areas mediating low- and mid-level visual motion processing. They also suggest that adaptation is an active process that involves neural mechanisms operating at different time scales. In Experiments 2 and 3, the short-term adaptation induced changes over these identified scalp sites were further examined based on Experiment 1. Given that the phi and reverse-phi motion mainly engage within (ON or OFF) and across (ON and OFF) pathway mechanisms, the comparisons of adaptation induced changes across these motion types provided further insights into the nature of corresponding mechanisms over the visual cortex. The behavioral and EEG findings pointed to the efficient convergence of information provided by these pathways and some distinct characteristics of across pathway mechanisms.
Identification of preclinical implications for novel indole-benzimidazoles and phenothiazines using in vitro cancer cell line and in vivo zebrafish models
Meme kanseri (BC) ve hepatosellüler karsinom (HCC), kayda değer ölüm oranlarına sahip iki önemli sağlık sorunudur. İlaç tedavileri mevcut olmasına rağmen, terapötik başarı sınırlıdır. Düşük biyoyararlanım, yüksek toksisite ve tekrarlayan ilaç direnci nedeniyle yeni tedavi seçenekleri gereklidir. Bu tezde, BC ve HCC'de, sırası ile, yeni indol-benzimidazol ve fenotiyazinlerin anti-kanser etkilerini ve klinik öncesi potansiyellerini test etmek için farklı in vitro, in siliko ve in vivo yaklaşımlar uygulandı. Tezin ilk bileşeninde, in vitro kanser hatları, in vivo zebrabalığı embriyo ve larvaları ve in siliko karşılaştırmalı transkriptomik analizler kullanarak yeni indol-benzimidazol türevlerinin BC hücre hattı toksisitelerini ve östrojen reseptörü (ER) ile ilişkilerini değerlendirdim. İkinci bölümde ise antipsikotik bileşikler olan fenotiyazinler (PTZ), HCC tedavisi için yeniden konumlandırıldılar. Bu nedenle, tek başına veya sorafenib (SFB) ile kombinasyon halinde jenerik PTZ türevleri, in vitro kanser hatları, ardından zebrabalığı gelişim testleri ve embriyonik aşama zenograftları kullanılarak test edildiler. Ek olarak, RNAseq analizleri, ilaçların gen ekspresyon düzeyindeki sinerjistik/antagonistik etkilerini anlamak üzere trifluoperazin (TFP), SFB ve TFP + SFB kombinasyonu ile muamele edilen Hep3B hücreleri üzerinde gerçekleştirildi. Son olarak, yeni PTZ türevlerinin anti-HCC potansiyelleri, in vitro ve in vivo taramalarla araştırıldı. Ayrıca, yeni ve jenerik türevlerin nöral yolaklar üzerindeki etkileri, kolinesteraz testleri ve motor tepki ölçümleri ile değerlendirildi. Tezin bulguları, özgün BC ve HCC tedavilerine istinaden ileri klinik öncesi çalışmaların yürütülmesine potansiyel yol gösterici niteliktedir.
Zebrabalığı (danio rerio) beyninde yaşlanma, diyet ve olası genetik müdahalelerin SMURF2 ve etkileşim ortaklarının ifadesine etkileri
Aging is a natural process that is ultimate combination of numerous intrinsic and extrinsic changes in an organism. Contrary the common belief, brain aging is not a loss of neurons while it has been shown that subtle cellular and synaptic alterations have contribution to brain aging. Therefore, the molecular and cellular alterations may give more insight into the brain aging process. There are some hallmarks of aging that are common features in different organisms including genomic instability, telomere attrition, cellular senescence. There are some common factors with the ability to regulate more than one of the hallmarks of aging such as Smurf2. HECT-domain E3 ubiquitin ligase Smurf2 has several roles in the cellular processes for example, telomere attrition and cellular senescence. Moreover, its gene expression is higher in the aged brain. Although there are several publications about Smurf2, most of them focused on its role in cancer. We believed that Smurf2 levels should be examined in terms of brain aging. The first aim of the study was to examine the levels of Smurf2 and its interacting partners across lifespan. Although the Smurf2 protein level was not increased significantly in the whole zebrafish brain, its protein level was upregulated significantly in telencephalon and cerebellum. Also, subcellular protein fractionation demonstrated an enriched Smurf2 level in the cytosolic part. In the case of gene expression levels, smurf2 level was significantly higher in aged whole brain although its expression was downregulated during aging in telencephalon and cerebellum. In addition, the levels of mdm2, ep300a and sirt1 were lower in the aged telencephalon. According to multivariate analysis there is a potential balance between Smurf2-mediated ubiquitination, ep300a-mediated acetylation and Sirt1-mediated deacetylation but with advancing age, this balance may disrupt and other regulatory genes should also take a role to sustain cellular stability. The second aim was to investigate the roles of Smurf2 on brain aging with the help of genetic interventions including inducible knockin, stable knockout or transient knockdown. Since stable knockin and knockout models should be genotyped before further investigations, the genotyping and phenotyping methods were employed to find an efficient and reliable way. Also, transient knockdown via Vivo-morpholino was applied to adult brain and efficient post injection times of two different morpholinos were identified in order to examine the effects of Smurf2 knockdown in both young and old zebrafish. Lastly, it was aimed to examine the effects of non-genetic interventions including dietary regimens and pharmacological compounds on the gene expression of smurf2 and its interacting partners and the levels of the neuronal proteins and proliferation/senescence proteins. The opposing short-term dietary regimens, overfeeding and caloric restriction, were altered the levels of neuronal proteins, HuC and DCAMKL1, and their relation with proliferation and senescence proteins during aging. Also, the gene expression levels of smurf2 and interacting partners except tp53 was not influenced by dietary regimens and aging in terms of whole brain. Also, multivariate analysis indicated that the correlations among smurf2, mdm2, ep300a and sirt1 were conserved in both young and old ages independent to dietary regimen which may imply that the balance between ubiquitination, acetylation and deacetylation is maintained in order to provide cellular stability during aging. Heclin, an inhibitor of HECT E3 ligases, were employed to inhibit Smurf2 activity. Before using in adult zebrafish, heclin was applied to embryos to see its effects. The higher dose of heclin decreased the survival ratio and altered the gene expression levels of downstream gene drastically. So, moderate dose of heclin should be applied to the adult brain and neuronal markers should be examined to observe target effects rather than off-target, unspecific impacts. Taken together, Smurf2 has potential roles during aging and it could be a promising target to delay the brain aging process and probably the onset of age-related cognitive decline.
Değişen düzey ve farklı sürelerdeki kalori kısıtlamasının hücresel ve sinaptik proteinler ve dişi fare beyninin inflamatuvar durumu üzerine etkileri
Aging is an inevitable and complicated process leading to functional decline. Regarding brain aging, cognitive decline takes place in multiple domains, including learning, memory, executive functions, motor coordination, and language. At the cellular and molecular level, age-related cognitive decline is elucidated with certain hallmarks, including aberrant neuronal network, stem cell exhaustion, glial cell activation, and inflammation. Calorie restriction (CR) is a widely-utilized approach for coping with aging's detrimental effects even though there is no one agreed way for the application of CR. In this study, varying levels of CRs were applied for differing durations to MMTV-TGF-alpha female mice. The study initiated when mice were 10-weeks of age (Baseline) and carried out until 49/50 weeks of age and 81/82 weeks of age. There were four dietary groups named Ad-libitum (AL; control), Chronic Calorie Restriction (CCR), Intermittent Calorie Restriction - Restriction (ICR-R), and Intermittent Calorie Restriction -Refeed (ICR-RF). The study's first aim was to show age-related changes in the cellular and synaptic proteins and the inflammatory state of the female mice's brains. The second aim of the study is to demonstrate the effects of varying levels of CR implemented for the short-term and the long-term manner on the same hallmarks. Our findings showed both chronic- or intermittent- CR altered the synaptic integrity proteins against brain aging at the long-term period (81/82 weeks) compared to the short-term (49/50 weeks) period except for PSD-95. Similarly, both chronic- or intermittent- CR showed an attenuative impact on the pro-inflammatory markers, but IL-6 was affected only by CCR at the same periods. Furthermore, an age-related imbalance between neurogenesis and astrogliogenesis was shown based on DCX and GFAP. Both chronic- or intermittent- CR showed a compensatory effect on it acting through astrogliogenesis, even though it was not statistically significant.
Ergenlik-erken yetişkinlik döneminde dorsolateral prefrontal kortekste gerçekleşen dinamik alternatif gen kırpılma olayları ve şizofreni ile ilgili çıkarımlar
Alternative splicing (AS) or differential exon usage (DEU) is a regular process after gene expression and it contributes to the diversity of the genome by generating multiple protein isoforms. According to recent studies, the majority (92-94\%) of all human multi-exon genes undergo AS and the brain, especially the neocortex, has the highest number of AS events compared to other tissues. While contributing to the complexity of the brain, AS may lead to neuropsychiatric disorders such as schizophrenia or autism if dysregulated. Adolescence and young adulthood (AYA) period which nearly covers age range between 15 to 24 years old, is known to be a critical time to develop several neuropsychiatric disorders including schizophrenia and depression. Therefore, it is important to know developmental changes in AS events that occur in healthy brains in order to understand what is disrupted in a diseased brain. Although there are many studies investigating the possible roles of AS in the function of specific neuron types and during neurogenesis, there are only a few studies investigating AS changes in the human brain during different developmental periods. Therefore, in this study we first compared DEU that occur in the dorsolateral prefrontal cortex (DLPFC) of psychologically healthy individuals during AYA period to other developmental periods: infancy, early childhood, middle and late childhood, young adulthood, middle adulthood, and late adulthood. Additionally we compared DEU that occur in the DLPFC of schizophrenia patients to psychologically healthy individuals. Then we found exons that show both developmental and schizophrenia related DEU changes. Our results revealed 4 exons that belong to 3 different genes: AKAP7, BAIAP3 and SEMA3B. If further investigated, these exons can help us better understand the pathophysiology of schizophrenia and be possible early markers of the disease.
Bipolar bozuklukta farklı eksprese genlerin analizi: Çalışma belleği ile ilgili bölgelerde ergenlik ve genç erişkinliğin transkriptom imzası
Bipolar 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 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 identifi ed common genes and pathways from the results of different analyses. As a result of this comparison, while six genes were identi fied diffrentially 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 signifi cant biological pathways might be influenced by the treatment.
Algısal öğrenmenin görsel korteksin işlevi ve mikro yapısı üzerindeki etkilerinin araştırılması
Perceptual learning is the long-term improvement of the ability to process sensory stimuli through experience. Although an extensively studied field, the mechanism and locus of plasticity underlying visual perceptual learning is subject of debate. Here, we investigated the experience-dependent plasticity in the visual cortex across the time course of perceptual learning of bisection discrimination task. Population receptive field (pRF) analysis was used to examine functional architecture of the visual cortex. Microstructural properties of the visual cortex were characterized with neurite orientation dispersion and density imaging (NODDI). We compared pre-, mid-, and post-training values of pRF size, neurite density, and orientation dispersion in the trained location as well as in two control locations where no training has been received. The values in the trained location did not change with time and did not differ from control locations. In addition, we assessed the microstructural properties in the white matter tract between the training location and the mirror-symmetric control location and did not observe any change with training. In conclusion, we found no training-related changes in the early visual cortex (V1-V3). Our results are limited by the lack of performance improvement with training and the small sample size. Moreover, we were not able to identify visual areas beyond V1-V3 leaving high-level visual areas unexplored. Suggestions for further research include redesigning the behavioral training paradigm, optimization of pRF protocol to identify high-level visual areas, and repeating the study with a larger sample size.
Zebra balığı (Danio rerio) model organizması kullanılarak yaşlanmanın beyindeki inflamatuar, hücre iskeleti, ve mikroglia belirteçlerindeki gen ifade düzeyleri üzerine etkileri
Age-related cognitive decline burdens the elderly population, limiting their ability to socialize and be independent. To be able to develop proper treatments, healthy aging should be examined. Previous studies focusing on healthy brain aging revealed that abnormal microglial activation was observed. Aging microglia exhibits 0partial loss of motility due to cytoskeletal changes, leading to decreases in their ability to respond to environmental cues. Thus, a more inflammatory phenotype was observed in microglia. These disruptions of the previously established homeostasis in the brain could be the underlying reason for cognitive decline experienced during aging. To understand these changes during aging in the brain, cytoskeletal, microglial, and inflammation-related markers were investigated by using both in silico and in vivo approaches. In silico analyses were performed on mice hippocampus and the whole brain revealed that the genes involved in the actin cytoskeleton reorganization (Arpc1b), neurogenesis (Erbb4), and proinflammatory related pathways (Il1b, P2x7r, Elf2b) showed differential gene expression levels among different age groups, genders, and tissue of origin. On the other hand, no differential expression was observed in microglial (Coro1a and Aif1) and anti-inflammatory markers (Tgfb1 and Il10). To further validate these results in vivo, quantitative polymerase chain reaction (qPCR) was performed on young and old zebrafish brains. According to the results, only two genes showed marginally significant differences among young and old brains: arpc1b and p2x7r. These results collectively could mean 1) the overall microglia population does not change during aging, 2) the brain does not exhibit imbalances in terms of pro- and anti-inflammatory cytokines, and 3) neurogenesis. Furthermore, the significant changes observed in arpc1b and p2x7r indicated the iii iv importance of the cytoskeleton and inflammation-related pathways in the correct functioning of the cells. Therefore, this study showed that in silico analysis are the reliable indicators of in vivo experiments, zebrafish can be used as a gerontological model, and the importance of cytoskeleton in motile cells. However, to understand these described relations, further investigation on the protein level of these genes should be done.
Yaşlanan zebra balığında hareket tespitinin optomotor yanıt ile incelenmesi
Various aspects of visual functioning including motion perception have been shown to be significantly altered throughout aging. Contrary to the traditional view focusing on structural changes in the eye and retina, accumulating evidence suggests that subtle alterations in neural circuitry and functioning are responsible for the age-related changes in visual sensitivity and perception. However, the mechanisms underlying age-related changes in motion perception are still poorly understood. This thesis was aimed to investigate the detection of first- and second-order motion direction during aging by using zebrafish optomotor responses (OMR). Furthermore, exposure-based visual learning was investigated by repeated presentation of first-order motion. The studies included both wild-type and achesb55/+ zebrafish with decreased levels of acetylcholinesterase which has been previously shown to delay age-related cognitive decline. In this way, it was also aimed to explore the possible functional links between cholinergic functioning and age-related changes in visual motion processing. The results indicated that adult zebrafish mainly exhibit negative OMR (i.e., position shift in the opposite direction of visual motion) to drifting first-order gratings which is significantly dependent on spatial frequency and contrast level of the motion. Rather than an overall effect of aging, the results revealed a three-way interaction between the contrast level of first-order motion, genotype, and age. Therefore, the findings pointed out a complex relationship between the physical characteristics of first-order motion stimulation and the cholinergic system during neural aging. Contrary to the first-order motion, the second-order motion did not induce strong optomotor responses in adult zebrafish. Although young and old zebrafish exhibited OMR with different polarities (negative and positive OMR, respectively), future work revealing robust responses will be informative to better understand and characterize age-related changes. Lastly, passive exposure of repeated first-order motion induced significant improvements in negative OMR of young and old zebrafish, suggesting that adult zebrafish can be used as a model organism to study passive forms of visual perceptual learning. Overall, these behavioral results pave the way for a detailed investigation of the functional links between the physical motion characteristics and the cholinergic system in the zebrafish aging model which will ultimately have important implications for developing interventions to improve human visual performance during aging.
Kontrast oranının metakontrast maskeleme üzerindeki etkilerinin nörofizyolojik olarak incelenmesi
Visual masking has been used as an investigative tool to understand the dynamics of sensory and perceptual processing. Given that masking can also cause aware and unaware visual conditions, it has also found applications in visual awareness studies. Metacontrast is a common type of visual masking in which the target visibility is suppressed by presenting a following and spatially adjacent mask. However, the neural correlates of this common masking type are still open to discussion. Accordingly, the current thesis examined the influences of mask-to-target (M/T) contrast ratio on metacontrast masking using electroencephalography (EEG). A contour discrimination task was employed to assess target visibility under different M/T contrast ratios and stimulus onset asynchronies (SOAs). The behavioral results indicated U-shaped masking functions with strong target visibility suppression at intermediate SOA values for both low and high contrast ratios. Importantly, the contrast ratio significantly altered the suppression amount (i.e., the amount of masking effect) at these SOAs. Relying on these modulations, we analyzed EEG data and focused on VAN (visual awareness negativity, around 140-200 ms and 200-300 ms) and LP (late positivity, around 300-550 ms) components. In the VAN component range of 200-300 ms, we found an SOA dependency in evoked potentials. For all the component time ranges, the contrast ratio did not reveal significant alterations in evoked potentials. Taken together, these findings highlight the significant modulations of contrast ratio on metacontrast masking at intermediate SOA values. Nevertheless, these alterations were not indicated by the studied event-related potentials and components.
Uzaysal destekli voksel-bazlı modelleme ve insan beyninde dinamik sahne kategorisi temsili
Humans have an impressive ability to rapidly process global information in natural scenes to infer their category. Yet, it remains unclear whether and how scene categories observed dynamically in the natural world are represented in cerebral cortex beyond few canonical scene-selective areas. To address this question, here we examined the representation of dynamic visual scenes by recording whole-brain blood oxygenation level-dependent (BOLD) responses while subjects viewed natural movies. We fit voxelwise encoding models to estimate tuning for scene categories that reflect statistical ensembles of objects and actions in the natural world. Voxelwise modeling (VM) is a powerful framework to predict single voxel responses evoked by a rich set of stimulus features present in complex natural stimuli. However, because VM disregards correlations across neighboring voxels, its sensitivity in detecting functional selectivity can be diminished in the presence of high levels of measurement noise. Here, we introduce spatially-informed voxelwise modeling (SPIN-VM) to take advantage of response correlations in spatial neighborhoods of voxels. To optimally utilize shared information, SPIN-VM performs regularization across spatial neighborhoods in addition to model features, while still generating single-voxel response predictions. Compared to VM, SPIN-VM yields higher prediction accuracies and better capture locally congruent information representations across cortex. We find that this scene-category model explains a significant portion of the response variance broadly across cerebral cortex. Cluster analysis of scene-category tuning profiles across cortex reveals nine spatially-segregated networks of brain regions consistently across subjects. These networks show heterogeneous tuning for a diverse set of dynamic scene categories related to navigation, human activity, social interaction, civilization, natural environment, non-human animals, motion-energy, and texture, suggesting that the organization of scene category representation is quite complex.
Nöropsikiyatrik belirtilerden önce pediatrik sistemik lupus eritematozus'ta yapısal bağlantı değişiklikleri
Systemic lupus erythematosus (SLE) is an autoimmune multi-system disorder affecting the central nervous system which may exhibit neuropsychiatric manifestations. Pediatric-onset SLE is rare and although there is an increased risk of neuropsychiatric symptoms, underlying pathological mechanisms remain poorly understood. This study explored the entire white matter network with brain structural connectivity and DTI tractography analysis to provide a better understanding of the probable connectivity alterations. Whole-brain structural connectivity and tractography of 17 pediatric-onset SLE patients without neuropsychiatric involvement (non-NPSLE) and 8 age and gender matched healthy controls were explored. To investigate the topological structure, graph theory analysis was applied. Global and nodal network features were derived by estimating structural connectivity matrices between 360 brain regions of the HCP atlas. Non-NPSLE patients demonstrated higher network characteristic path length and assortativity and lower density and global efficiency compared with healthy controls. The hubs were selected according to the strength of the nodes and their structure and distribution were changed in the patients. According to the altered hubs' network characteristics significant modifications between HCs and non-NPSLE, along with TBSS findings, altered regions were observed in the language, visual, auditory, and motor-related areas. These findings are in good agreement with WISC-IV VerbalComprehension Index. Compared to healthy controls non-NPSLE patients showed significantly lower scores according to WISC-IV score components. To conclude, from a network and connectivity perspective, our research demonstrated an altered topological structure of the brain in non-NPSLE patients. The findings of this study provide a better understanding of the structural alterations underlying pediatric-onset non-NPSLE patients' functional and neurocognitive abnormalities.
Dikkat yükü altında biyolojik hareket algısının nöral temelleri
Humans can detect and differentiate biological motion from non-biological motion stimuli effortlessly, even if the stimuli were shown as simplistic as a composition of moving dots (i.e. point-light displays [PLD]). Considering its survival and social significance, BM perception is assumed to occur automatically. Indeed, Thornton and Vuong (2004) showed that task-irrelevant BM in the periphery interfered with task performance at the fovea. However, the neural underpinnings of this bottom-up processing of BM lacks thorough examination in the field. Under selective attention, BM perception is supported by a network of regions including the occipito-temporal, parietal, and premotor cortices. A retinotopy mapping study on BM showed distinct maps for its processing under and away from selective attention (Saygın & Sereno, 2008). Based on these findings, we investigated how bottom-up perception of BM would be processed under attentional load when it was shown away from the focus of attention as a task-irrelevant stimulus. Participants (N=31) underwent an fMRI study in which they performed an attentionally demanding visual detection task at the fovea while intact or scrambled PLDs of BM were shown at the periphery. Our results showed the main effect of attentional load in fronto-parietal regions; as well as, the main effect of peripheral stimuli in occipito-temporal cortex. Both univariate and multivariate pattern analysis results support the attentional load modulation on BM. Lastly, ROI results on each core node of BM processing network expanded these findings by showing that the attentional load modulation on both intact and scrambled BM stimuli were the strongest in bilateral occipito-temporal regions as compared to parietal and premotor cortices. In conclusion, BM was processed within the motion sensitive regions in the occipito-temporal cortex when shown away from the selective attention, and was modulated by attentional load.
Dinamik görmenin dikkat modülasyonlarının temelindeki kortikal süreçler
Visual 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.
Çalışma belleği kapasitesi: Eşzamanlı görevler birbirine ket vurmak zorunda değil
Any extended task episode is subsumed by goal-directed programs that hierarchically control its execution. We investigated the relationship between working memory capacity and the control instantiated by such hierarchical task entities across four experiments. In a new extended task consisting of subtask A and subtask B, participants first memorized the orientation of subtask A lines (let's call this event mA), then memorized subtask B lines (mB), then recalled these B lines (rB), and finally recalled A lines (rA). The task structure was: mA-mB-rB-rA. Subtask A lines were thus held in mind during the execution of subtask B. Even though participants had to remember the orientation of lines in both cases, increased WM load of lines A only affected performance on subtask A and did not affect the performance on subtask B. In Experiment 2, four trials of Exp1 were organized into a complex 4-part task with the added condition that A lines of a part be recalled not in that part but in the next part. The task structure was: mA1-mB1-rB1—mA2-mB2-rB2-rA1—mA3-mB3-rB3-rA2—mB3-rB3-rA3. Load of A lines again did not affect B lines. Crucially, load of A2 and A3 lines did not affect the recall of A1 and A2 lines, respectively. In Experiment 3, in a design similar to Exp1, time constraint on mA and mB increased the interference across concurrent subtasks. Experiment 4 showed that increasing the similarity between subtask A and subtask B of Exp1 may increase the across-subtask interference. We show that WM information of different concurrent subtasks can be maintained separately, perhaps as part of their goal-directed programs. And, encoding to these non-interfering stores, as well as retrieval from them, might depend on attentional and time-based mechanisms.
Yeni kelime öğrenimi sırasında tahmine dayalı işleme: Ünlü uyumu olaya ilişkin potansiyelleri
This project investigated the effect of Turkish vowel harmony (TVH) on the acquisition of multi-syllabic words via cross-situational word learning (CSWL). CSWL is an implicit learning paradigm requiring learners to statistically track word-referent pairs across ambiguous conditions. Although there are many studies have examined certain lexical conditions that span word boundaries, within-lexical unit characteristics, such as TVH, have not been examined. We conducted 2 experiments; Experiment 1 is an internet-based experiment with Native Turkish speakers and speakers of other languages, and Experiment 2 is an EEG experiment focusing on N400 and LPC ERPs with Native Turkish speakers. In experiment 1, participants received training and recognition test phases. During training, participants were presented with novel pseudowords, both harmonious and disharmonious for TVH, with multiple referent pictures. In the recognition test, participants heard a pseudoword and were asked to select the correct referent for it. The results of the first experiment did not show a significant difference. In experiment 2, learning was additionally measured by a semantic judgment task (SJT). In the SJT, participants were presented with either a learned pseudoword or a real Turkish word, then with another real Turkish word. Their task was to indicate whether the two presented words were from the same semantic category. The recognition test results showed high accuracy, implying successful learning, with no differences among TVH conditions. The SJT results were modulated by both the novelty of the words (pseudowords vs. real words) and the harmony conditions in both behavioral and ERP measures. Specifically, harmonious words lead to N400 responses similar to real words, with no such effect on the disharmonious words. These results suggest that the phonological rules of participants' native language had an impact on semantic consolidation.
Aktör algılama sürecinde görsel belirsizliği çözmede ön bilgi ve hareket ipuçlarının etkileşimi
Agent perception, a complex cognitive task that involves interpreting an agent's actions to infer their internal states and adjust our behavior accordingly, is a fundamental aspect of human cognition. Despite its importance, a significant gap persists in our understanding of how low-level factors, such as motion and form information, interact with top-down factors, such as prior information about the agents. To address this gap, we conducted two electroencephalogram (EEG) experiments investigating the interplay of prior knowledge and motion information on the temporal dynamics of agent perception in the human brain. We used human, android and robot agents engaged in various actions. The chosen agents were designed to form a set wherein form information alone could not easily resolve the ambiguity in agent identities. In the first experiment, participants were informed about agent identities before the experiment (Prior Experiment), while in the second experiment, participants remained uninformed (Naive Experiment). We controlled the availability of motion information by presenting stimuli in either video and image formats. We recorded scalp EEG and utilized event-related potential (ERP) analysis and model-based representational similarity analysis (RSA) to uncover the temporal course of agent representation in the human brain. Our results revealed that the processing of agents in EEG depends on the availability of motion information and prior information. Specifically, in the Naive Experiment, agent information was available longer during the still condition than in the moving condition. In contrast, agent information was present for similar durations in still and moving conditions of the Prior Experiment. These findings suggest that prior knowledge and motion information interactively modulate the duration of the processing of agent information. Our results underscore the critical role of prior knowledge and motion cues in shaping the processing of agent information, highlighting the complex interplay between top-down modulation and bottom-up cues in driving the perception of agents and their actions. This study contributes to our understanding of the temporal dynamics of agent perception and the role of top-down and bottom-up processes in this complex cognitive task.
Varsayılan mod ve çoklu talep ağlarının aktivasyonu: İstemli ve istemsiz zihin gezintisi üzerine bir FMRI çalışması
Mind wandering or task-unrelated, self-generated thoughts happen every day in life. These thoughts can either be Unintentional or Intentional. The brain's Default Mode (DMN) and Multiple Demand (MD) networks integrate during Mind Wandering. In this study, we conducted a functional magnetic resonance imaging (fMRI) experiment where Mind Wandering was the task. During this task's think part, an Intentional form of Mind Wandering occurred. Meanwhile, Unintentional Mind Wandering took place during the rest part where participants rested in the fMRI machine. We aimed to see the difference in the pattern of activity in both the Default Mode and Multiple Demand Networks during the Intentional and Unintentional Mind Wandering. Our results showed that, in the Posterior Cingulate Cortex (PCC) and the left Temporoparietal Junction (TPJ) regions of the Default Mode Network, the think part provokes a stronger response than the rest part. On the other hand, the Multiple Demand network regions responded differently to the different forms of Mind Wandering. Some Multiple Demand regions, such as the left Inferior Frontal Sulcus (IFS) and the pre-Supplementary Motor Area (pre-SMA), represented a more robust response in the think part than the rest part. Meanwhile, the bilateral Intraparietal Sulcus (IPS) regions showed stronger activation in response to the rest part. In addition, we showed that the Language regions have a more pronounced activation in the think part than the rest part. Consequently, the Default Mode Network's regions, some of the Multiple Demand regions, and Language regions respond more robustly to the Intentional form of Mind Wandering than the Unintentional Mind Wandering.