Ovarian steroid hormones are known to produce several different effects in the brain. In addition to their role in gonadotropin release, ovulation and sexual behaviour they also seem to affect mood and emotions, as shown in women with the premenstrual tension syndrome. Some steroids have the ability to affect brain excitability. Estradiol decreases the electroshock threshold while progesterone acts as an anti-convulsant and anaesthetic in both animals and humans. Several earlier studies have shown a specific uptake of several steroids in the animal brain but only a few recent studies have established the presence of steroids in the human brain. In the present studies, the dissections of rat and human brains were carried out macroscopically and areas that are considered to be related to steroid effects were chosen. Steroid concentrations were measured by radioimmunoassay after extraction and separation with celite chromatography. The accuracy and specificity of these methods were estimated. In the animal studies, immature female rats were treated with Pregnant Mare's Serum Gonadotropin (PMSG) to induce simultaneous ovulations. Concentrations of estradiol and progesterone were measured in seven brain areas pre- and postovulatory. The highest concentration of estradiol, pre- and postovulatory, was found in the hypothalamus and differences between the two cycle phases were detected in most brain areas. The preovulatory concentrations of progesterone were low and the highest postovulatory concentration was found in the cerebral cortex. In one study, the rats were injected with pharmacological doses of progesterone to induce "anaesthesia". High uptake of progesterone was found and a regional variation in the formation of 5&lt;*-pregnane-3,20-dione in the brain with the highest ratio in the medulla oblongata. Concentrations of progesterone, 5a-pregnane-3*20-dione, estradiol and testosterone were determined in 17 brain areas of fertile compared to postmenopausal women. All steroids displayed regional differences in brain concentrations. Higher concentrations of estradiol and progesterone were found in the fertile compared to the postmenopausal women. In summary, these studies show that the concentrations of ovarian steroids in the brain are different at different endocrine states in both rats and humans and that there are regional differences in brain steroid distribution. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1987, härtill 5 uppsastser</p> / digitalisering@umu

Human neurodevelopment requires the coordinated expression of thousands of genes, exquisitely regulated in both spatial and temporal dimensions, to achieve the proper specialization and inter-connectivity of brain regions. Consequently, the dysregulation of complex gene networks in the developing brain is believed to underlie many neurodevelopmental disorders, such as autism spectrum disorders (ASD). Autism has a significant genetic etiology, but there are hundreds of genes implicated, and their functions are heterogeneous and complex. Therefore, an understanding of shared molecular and cellular pathways underlying the development ASD has remained elusive, hampering attempts to develop common diagnostic biomarkers or treatments for this disorder. I hypothesized that analyzing functional genomics relationships among ASD candidate genes during normal human brain development would provide insight into common cellular and molecular pathways that are affected in autistic individuals, and may help elucidate how hundreds of diverse genes can all be linked to a single clinical phenotype. This thesis describes a coordinated set of bioinformatics experiments that first (i) assessed for gene expression and co-expression properties among ASD candidates and other non-coding RNAs during normal human brain development to discover potential shared mechanisms; and then (ii) directly assessed for changes in these pathways in autistic post-mortem brain tissue. The results demonstrated that when examined in the context of normal human brain gene expression during early development, autism candidate genes appear to be strongly related to the neurodevelopmental pathways of synaptogenesis, mitochondrial function, glial cytokine signaling, and transcription/translation regulation. Furthermore, the known sex bias in ASD prevalence appeared to relate to differences in gene expression between the developing brains of males and females. Follow up studies in autistic brain tissue confirmed that changes in mitochondrial gene expression networks, glial pathways, and gene expression regulatory mechanisms are all altered in the brains of autistic individuals. Together, these results show that the heterogeneous set of autism candidate genes are related to each other through shared transcriptional networks that funnel into common molecular mechanisms, and that these mechanisms are aberrant in autistic brains.

Previous findings from this laboratory demonstrating changes in dopamine (DA) transporter and D2 receptors in the amygdaloid complex of subjects with major depression indicate that disruption of dopamine neurotransmission to the amygdala may contribute to behavioral symptoms associated with depression. Quantitative real-time RT-PCR was used to investigate the regional distribution of gene expression of DA receptors in the human amygdala. In addition, relative levels of mRNA of DA receptors in the basal amygdaloid nucleus were measured postmortem in subjects with major depression and normal control subjects. All five subtypes of DA receptor mRNA were detected in all amygdaloid subnuclei, although D1, D2, and D4 receptor mRNAs were more abundant than D3 and D5 mRNAs by an order of magnitude. The highest level of D1 mRNA was found in the central nucleus, whereas D2 mRNA was the most abundant in the basal nucleus. Levels of D4 mRNA were highest in the basal and central nuclei. In the basal nucleus, amounts of D4, but not D1 or D2, mRNAs were significantly higher in subjects with major depression as compared to control subjects. These findings demonstrate that the D1, D2 and D4 receptors are the major subtypes of DA receptors in the human amygdala. Elevated DA receptor gene expression in depressive subjects further implicates altered dopaminergic transmission in the amygdala in depression.

京都大学 / 0048 / 新制・論文博士 / 博士(人間健康科学) / 乙第13143号 / 論人健博第4号 / 新制||人健||4(附属図書館) / (主査)教授 精山 明敏, 教授 澤本 伸克, 教授 伊佐 正 / 学位規則第4条第2項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21010号 / 医博第4356号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上 治久, 教授 村井 俊哉, 教授 林 康紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In this paper, I examine if strong artificial intelligence can be achieved or not. Can machines have a mind, be conscious, think and have subjective experiences, just like a human? I analyze David Chalmers arguments supporting the possibility of strong AI and conclude that his emulation argument and principle of organizational invariance is not a sufficient condition for strong AI. Instead, I defend the thesis that life is a necessary condition for any conscious agent, human or machine (or other), to have a mind, be able to think and have subjective experiences. I revisit the ideas of the soul and of vitalism and the need for a life force energy, an élan vital as introduced by Henri Bergson. In the investigation of life I also examine if strong artificial life can be achieved or not, since this would be a prerequisite for strong AI.

The study of brain nuclei in neuroimaging poses challenges owing to its small size. Many neuroimaging studies have been reported for effectively locating these nuclei and characterizing their functional connectivity with other regions of the brain. Hypothalamus, Locus Coeruleus, and Ventral Tegmental area are such nuclei found in the human brain, which are challenging to visualize owing to their size and lack of tissue contrast with surrounding regions. Resting-state functional magnetic resonance imaging (rsfMRI) analysis on these nuclei enabled researchers to characterize their connectivity with other regions of the brain. An automated method to successfully isolate voxels belonging to these nuclei is still a great challenge in the field of neuroimaging. Atlas-based segmentation is the most common method used to study the anatomy and the functional connectivity of these brain nuclei. However, atlas-based segmentation has shown inconsistency due to variation in brain atlases owing to different population studies. Therefore, in this study, we try to address the research problem of brain nuclei imaging using a clustering-based approach. Clustering-based methods separate of voxels utilizing their structural and functional homogeneity to each other. This type of method can help locate and cluster the voxels belonging to the nuclei. Elimination of erroneous voxels by the use of clustering methods would significantly improve the structural and functional analysis of the nuclei in the human brain. Since several clustering methods are available in neuroimaging studies, the goal of this study is to find a robust model that has less variability across different subjects. Non-parametrical statistical analysis was performed as functional magnetic resonance imaging (fMRI) based studies are corrupted with noise and artefact. Statistical investigation on the fMRI data helps to assess the significant experimental effects.

yes / BACKGROUND AND PURPOSE Aging of the healthy brain is characterized by focal or nonfocal white matter (WM) signal abnormality (SA) changes, which are typically detected as leukoaraiosis (LA). Hypertension is a risk factor for WM lesion formation. This study investigated whether LA might be associated with increased cerebrospinal fluid (CSF) pulsatility linked to arterial hypertension. METHODS A total of 101 individuals without neurologic diseases (53 females and 48 males) aged between 18 and 75 years underwent 3T brain MRI with cine phase contrast imaging for CSF flow estimation, after providing their informed consent. LA was defined as the presence of focal T2 WM SA changes and/or nonfocal uniform areas of signal increase termed dirty appearing white matter (DAWM). Relevant information relating to cardiovascular risk factors was also collected. RESULTS When controlled for age and hypertension, significant partial correlations were observed between: DAWM volume and: net negative flow (r = –.294, P = .014); net positive flow (NPF) (r = .406, P = .001); and peak positive velocity (r = .342, P = .004). Multiple linear regression analysis revealed DAWM volume to be significantly correlated with CSF NPF (P = .019) and hypertension (P = .007), whereas T2 WM SA volume was only significantly correlated with age (P = .002). Combined DAWM and T2 WM SA volumes were significantly related with age (P = .001) and CSF peak negative velocity (P = .041). CONCLUSIONS Rarefaction of WM leading to LA is a multifactorial process, in which formation of DAWM induced by hypertension and increased aqueductal CSF pulsatility, may play a contributory role. These two factors appear to act independently of each other in a process that is independent of age.

Lipid oxidation is one of the leading causes of food quality degradation. Manufacturers typically add antioxidants or purge a product's package of oxygen to inhibit oxidation and the resulting off-flavors. Synthetic antioxidants (e.g. BHT, BHA) and some natural antioxidants (e.g. α-tocopherol) have found widespread use in this application. Unfortunately, the public views synthetic additives in a negative light and the current natural antioxidants have been unable to match the protection afforded by the synthetic antioxidants. The search for underutilized and natural antioxidants has led scientists to investigate many different plant-based extracts for use in food and in the treatment and prevention of disease. The objectives of this research were (1) to use ORAChromatography to identify peanut root extract fractions with high antioxidant capacity, (2) identification of compounds in peanut root extracts using HPLC and mass spectrometry, (3) test for the presence of aflatoxins in the extracts, (4) test peanut root extract in food model system for oxidation reduction capabilities, and (5) Testing peanut root extract's ability to decrease protein oxidation in cell culture. Crude peanut root extracts have high antioxidant activities that do not vary by cultivar. The ORAC activities of the peanut root fractions separated by HPLC with a C18 column varied (600.3 – 6564.4 μM TE/g dry extract), as did the total phenolic contents (23.1 – 79.6 mg GAE/g dry extract). Peanut root fractions had aflatoxins contamination well above the 20 ppb limit. Peanut root extracts and the known antioxidants tested were found to have no significant effect in inhibiting oxidation of peanut paste or HBMEC. Peanut root extracts were not shown to have any positive effects, but further research is necessary to eliminate peanut root extracts as a possible food ingredient and health supplement. / Ph. D.

Nos organes sensoriels sont sous un bombardement permanent d'informations provenant du monde extérieur dont seule une infime fraction est intéressante ou pertinente pour l'individu à chaque instant, comme par exemple le visage d'une personne recherchée au milieu d'une foule. Filtrer et extraire cette information sont des fonctions vitales du cerveau, mais les mécanismes neuronaux qui décident de la réussite ou l'échec de cette épreuve restent partiellement compris. La visée de ce projet est d'étudier la relation entre activité neurale de fond et performance comportementale dans des paradigmes nécessitant différents types d'attention, au moyen de techniques comportementales et de la neuroimagerie fonctionnelle. Le modèle théorique que j'évalue dans cette thèse postule une organisation hiérarchique de ces fonctions avec l'éveil comme fonction basique d'activation physiologique, la vigilance comme fonction intermédiaire et l'attention sélective comme niveau le plus élevé et spécifique. Nous proposons en outre que l'attention sélective et la vigilance emploient deux mécanismes orthogonaux ; ces deux versants du spectre attentionnel seront le focus des deux études expérimentales présentées dans ce manuscrit. Dans les deux cas, il s'agit de chercher un lien entre l'activité neuronale spontanée et la variabilité comportementale à travers des essais répétés.J'ai utilisé le paradigme de Stroop pour opérationnaliser l'attention sélective soumise à la distraction ; la couleur du mot écrit étant la cible et le mot lui-même un distracteur en conflit direct avec cette cible. Les résultats indiquent qu'une activité pré-stimulus plus élevée dans les aires frontales et ventrales pertinentes pertinentes pour la tâche corrèle essai par essai avec des temps de réponse plus rapides ; l’effet inverse est observé dans l’aire liée au traitement de la distraction (i.e. sensible à la forme des mots). De plus, la variabilité comportementale observée à travers les sujets corrèle avec la variabilité de l’effet préstimulus dans ces régions. Pour étudier la vigilance j’ai conçu un paradigme expérimental au cours duquel les sujets ont pour instruction de rapporter tout événement saillant dans la modalité auditive ou visuelle, sans aucun signal préparatoire permettant de prédire l’apparition du prochain stimulus ou sa nature. Confirmant nos résultats précédents, des temps de réactions plus rapides sont associés à une activité pré-stimulus plus élevée dans le réseau cingulo-thalamo-insulaire. De surcroît, une activité plus élevée dans le réseau du mode par défaut (DMN) est également associée à des réponses plus rapides alors que l’activité spontanée du réseau attentionnel dorsal (DAN) n’a aucun effet sur les temps de réaction aux essais visuels et un effet négatif sur ceux des essais auditifs. Des temps de réaction plus rapide sont également associés à une activité pré-stimulus plus élevée dans les aires sensorielles primaires, mais uniquement lorsque la modalité du stimulus subséquent est congruente avec l’aire de traitement sensoriel. Les conclusions générales qui découlent de cette thèse sont donc doubles : d’une part elle confirme la pertinence fonctionnelle des fluctuations neuronales spontanées pour le comportement, d’autre part elle apporte une première identification des structures neuronales impliquées dans la vigilance sans la confondre avec l’attention sélective. / How does the brain manage to efficiently select from the abundance of sensory input that information which is currently relevant, as, for example, a known face in a crowd? Filtering and extracting this information are essential functions of the brain, but the neural mechanisms underlying the success or failure of this cognitive operation are only partially understood. Together, the aim of this project is to study, using behavioral and imaging techniques, the relationship between spontaneous neural activity and behavioral performance in task settings involving several types of attention. The related working model I wish to assess in my thesis is that attentional functions are organized in a hierarchical manner, with arousal as a basic function, alertness as an intermediate function and selective attention as the highest and most specific level. I further propose that selective attention and tonic alertness employ two orthogonal mechanisms, those two sides of the attentional spectrum will be the focus of the two experiments presented in this manuscript. In both studies, our aim was to establish a link between spontaneous fluctuations of brain activity and behavioral variability across repeated trials I used the Stroop paradigm to operationalize selective attention under distraction, the target being the color of the ink in which the word is written, the word itself is then a distractor conflicting with the target. Results indicate that higher prestimulus activity in frontal and ventral regions relevant for the task correlates trial-by-trial with faster reaction times, the opposite effect is found in the area involved in the processing of distracting features (i.e. sensitive to the word form). Moreover, inter-subjects behavioral variability also correlated with the prestimulus effect variability in those regions. To study alertness, I designed an experimental paradigm where subjects are instructed to report whatever salient event occurs in the auditory or visual modality during the recording, without any preparatory cue allowing them to predict the timing or type of an upcoming stimulus. Confirming our previous results, faster reaction times were associated with a higher prestimulus activity in the cingulo-thalamo-insular network. Furthermore, higher prestimulus activity in the default mode network (DMN) was also tied to faster responses whereas dorsal attention network (DAN) activity was overall irrelevant and, on auditory trials, even detrimental to performance. Similarly, higher prestimulus activity in the primary sensory cortices was associated with faster responses, but those effects were confined to the respective modality or, for visual trials, most pronounced in the relevant retinotopic representation. The general conclusions resulting from this thesis are two-fold: first, it confirms the functional relevance of spontaneous neuronal fluctuations for behavior; on the other hand, it brings a first identification of the brain structures involved in alertness, without confusing it with selective attention.