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Yamanaka, Juri. "Anticipatory grip force control in stroke". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97235.
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When moving the arm while holding an object, grip force (GF) increases at movement onset (anticipatory control; AC). Post-stroke individuals preserve AC in some tasks but few of these have been ecological. We hypothesized that post-stroke individuals will have problems in AC during functional hand tasks. Subjects lifted a 63.5g load cell (lift) with the thumb and index finger and held it (hold) while flexing or extending the elbow (transport). GF, EMG activity of the elbow and thumb, and forearm acceleration were recorded. Stroke subjects had no impairments in AC between GF and acceleration. However, they used higher GF, had deficits in maintaining constant GF during hold, demonstrated abnormal couplings between GF and temporal parameters of grasp and had disrupted timing of muscle activation between thumb and elbow flexors during flexion movements. These findings suggest that people with stroke have disruptions in the patterns of grasping during functional arm tasks.Quand le bras en mouvement tient un objet, la force de préhension (FdP) augmente en début de mouvement (contrôle anticipatoire; CA). Après un accident vasculaire cérébral (AVC), les personnes conservent le CA dans quelques tâches mais peu d'entre elles sont écologiques. Nous avons émis l'hypothèse que l'AVC entraîne des problèmes de CA lors de tâches fonctionnelles. Les sujets ont levé un capteur de force de 63,5g (lever) avec le pouce et l'index et l'ont tenu (maintien) tout en fléchissant ou allongeant le coude (transport). La FdP, l'activité EMG des muscles du coude et du pouce ainsi que l'accélération de l'avant-bras ont été enregistrées. Les sujets avec un AVC n'avaient pas de déficience dans le CA entre la FdP et l'accélération. Toutefois, ils utilisaient plus de FdP; ils avaient des déficits dans le maintien de la FdP; ils ont démontrés des relations anormales entre la PdF et les paramètres temporels de préhension et ils présentaient une perturbation temporelle de l'activation musculaires entre le fléchisseurs du coude et du pouce lors des mouvements de flexion. Ces résultats suggèrent que les l'AVC altère les patrons de préhension lors de tâches fonctionnelles du bras.
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Leonard, Julia Anne. "The feedforward control of posture and movement". Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114142.
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Goal-directed arm movements performed in the standing position potentially disturb the body's equilibrium as a result of the multi-linked structure of the musculoskeletal system. To compensate for these disturbances and ensure that stability is maintained, the central nervous system (CNS) organizes postural adjustments preceding and accompanying the voluntary movement in a feedforward manner (Massion 1992) using knowledge of the dynamics of the body (Bouisset and Zattara 1981). To date, most studies investigating the control of posture during voluntary movements in humans have focused on either the role of the postural activity preceding the movement or on the temporal structure of these anticipatory postural adjustments (APAs) with respect to the focal movement. As such, detailed knowledge about the spatial organization of postural activity is lacking. Furthermore, it is not clear how posture is coordinated when the goal of a voluntary movement changes online. Therefore, the studies in this thesis were aimed at addressing these questions to develop a greater understanding of the organization of feedforward postural control during voluntary movements. Muscle activity, kinetics and kinematics were recorded as subjects performed unperturbed and perturbed reaching movements to targets located in multiple directions while standing. Feedforward postural control strategies preceding and accompanying the reaching movements were quantified. Characterization of the spatial and temporal patterns of muscle activity and ground reaction forces of postural adjustments preceding reach movements revealed that muscle activity was directionally-tuned to reach direction and forces that were constrained to two principal directions. Also, muscle synergies were able to explain the spatial and temporal variability in postural muscle activity in the period preceding the reaching movements, suggesting that a modular organization of muscle recruitment is adopted for this task. Overall, these strategies are similar to those observed for feedback postural responses, suggesting that the CNS relies on shared neural structures for controlling posture in both modes of control. Lastly, the nature of postural control was examined when reaching movements were perturbed with a shift of the visual target after the reaching movement was initiated. Here, muscle activity in the legs was consistently modulated prior to changes in the muscle activity related to the online correction of the arm trajectory.Taken together, the findings of this thesis provide important insights into how the brain coordinates the control of posture and movement. This work provides a measure of feedforward postural control strategies in healthy, young adults as a first step to understanding how and why deficits in balance control may occur during the execution of voluntary movements in fall-prone individuals.Les mouvements volontaires effectués dans la position debout peuvent engendrer des perturbations de l'équilibre en raison de la structure complexe du système musculo-squelettique. Pour amorcer ces perturbations et s'assurer que l'équilibre est maintenu, le système nerveux central (SNC) amorce le déplacement du centre de masse (CM) par la mise en jeu d'ajustements posturaux avant et accompagnant les mouvements programmés en mode proactif (Massion 1992) en utilisant des représentations internes du corps et de l'environnement. À ce jour, la majorité des études portant sur le contrôle de la posture lors des mouvements volontaires chez l'homme ont comme but soit l'identification du rôle ou la caractérisation de la structure temporelle de ces ajustements posturaux anticipateurs. Cependant, une connaissance approfondie concernant l'organisation spatiale de l'activité posturale est manquante. De plus, ce n'est pas évident comment la posture est coordonnée lorsque le but du mouvement change après le commencement du mouvement. Ainsi, les études présentées ici ont comme but de répondre à ces questions pour développer une meilleure compréhension de l'organisation centrale de la posture et le mouvement. Les signaux électromyographiques, les forces de réaction au sol et la cinématique tridimensionnelle ont été enregistrés pendant que les sujets effectuaient des mouvements de pointage vers des cibles distinctes dans la position debout. Les stratégies posturales organisées en mode proactif ont été quantifiées sans pertubations et avect des pertubations visuomotrices des movements d'atteinte. La caractérisation de l'organisation spatiale et temporelle de l'éléctromyographie et des forces appliquées au sol ont révélé que l'activité des muscles était biaisée vers la direction de pointage ('directionally-tuned') mais que les forces au sol étaient appliquées dans un nombre de directions limitées ('force constraint strategy'). De plus, la variabilité spatiale et temporelle de l'activité des muscles posturaux était expliquée par les synergies musculaires. Ceci suggère qu'une organisation modulaire est utilisée par le SNC pour faciliter la tâche de contrôle de la posture. Ces stratégies sont similaires à celles observées pour les ajustements posturaux compensatoires (à base de 'feedback' ou rétroaction), ce qui suggère que le SNC dépend des mêmes structures neuronales pour contrôler la posture dans la mode proactif et rétroactif. Par la suite, la nature du signal pour le contrôle de la posture a été examinée lors des mouvements de pointage qui ont été perturbés avec un déplacement de la cible visuelle après que le mouvement ait été commencé. Ici, l'activité musculaire dans les jambes était modulée avant la modulation de l'activité musculaire liée à la correction de la trajectoire du bras. Ensemble, les conclusions de cette thèse fournissent un aperçu important sur la façon dont le cerveau coordonne le contrôle de la posture et du mouvement. Les résultats présentés supportent la conclusion que les commandes centrales pour la posture et le mouvement interagissent dans le SNC, et que les structures neuronales sont partagées pour la posture organisée de façon anticipatoire, ou proactif, et compensatoire. Les stratégies posturales typiques dans les jeunes adultes en santé sont quantifiées et forment une base de données pour la comparaison avec des gens sujets au déséquilibre lors de la performance des mouvements volontaires.
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Bailey, Phoebe Elizabeth Psychology Faculty of Science UNSW. "The social cognitive neuroscience of empathy in older adulthood". Awarded By:University of New South Wales. Psychology, 2009. http://handle.unsw.edu.au/1959.4/44506.
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Empathy is an essential prerequisite for the development and maintenance of close interpersonal relationships. Given that older adults are particularly vulnerable to the negative consequences of loneliness and social isolation, it is surprising that few studies have assessed empathy in this group. The current programme of research addressed this gap in the literature by testing competing predictions derived from Socioemotional Selectivity Theory and the Ageing-Brain Model for age-related sparing and impairment of empathy, respectively. Study 1 compared young (N = 80) and older (N = 49) adults?? self-reported levels of cognitive and affective empathy, and engagement in social activities. It was found that although affective empathy is spared, cognitive empathy is subject to age-related decline, and this decline mediates reductions in social participation. These data therefore affirmed the importance of further investigation into the nature, causes and potential consequences of age-related differences in empathy. Since disinhibition is one mechanism contributing to difficulty taking the perspective of another, and is known to increase with age, in Study 2, behavioural measures sensitive to inhibitory failure and to cognitive empathy were administered to young (N = 36) and older (N = 33) adults. One of the measures of cognitive empathy directly manipulated inhibitory demands, involving either high or low levels of self-perspective inhibition. The results indicated that older adults were selectively impaired on the high-inhibition condition, with cognitive disinhibition mediating this association. Study 2 therefore provided important evidence relating to one potential mechanism that contributes to age-related difficulties in perspective-taking. Studies 3 and 4 provided the first behavioural assessments of age-related differences in affective empathy by using electromyography to index facial expression mimicry. Study 3 found that young (N = 35) and older (N = 35) adults?? demonstrate comparable mimicry of anger, but older adults?? initial (i.e., implicit) reactions were associated with reduced anger recognition. Thus, to test the possibility that despite explicit recognition difficulties, implicit processing of facial expressions may be preserved in older adulthood, Study 4 compared young (N = 46) and older (N = 40) adults?? mimicry responses to subliminally presented angry and happy facial expressions. As predicted, the two groups demonstrated commensurate subconscious mimicry of these expressions. Taken together, these studies indicate that separate components of empathy are differentially affected by healthy adult ageing. Implications for competing perspectives of socioemotional functioning in older adulthood are discussed.
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Wee, Caroline Lei. "Neuromodulatory Control of Motivated Behavior in the Larval Zebrafish". Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493507.
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An animal’s behavior is strongly influenced by homeostatic drives that are crucial for survival and reproduction, such as the drive to eat, or to escape from harmful threats. In vertebrates, an evolutionarily ancient brain structure, the hypothalamus, is particularly important for coordinating these essential survival functions. Here, I leverage the simple and transparent brain of the vertebrate larval zebrafish to dissect the conserved hypothalamic networks that regulate appetite and defensive behaviors, focusing on how these overlapping circuits interact with and influence each other.
By using an unbiased brain-wide activity mapping approach, I pinpoint hypothalamic oxytocin (OXT) neurons as a key hub for the control of defensive behaviors against pain. I show that OXT neurons integrate multiple noxious stimuli, in particular input from TRPA1 damage-sensing receptors, to drive pain avoidance behavior via co-release of OXT and glutamate in the hindbrain and spinal cord. Furthermore, OXT neurons can also integrate information about the animal’s social context to control appetite, a separate homeostatic drive. These findings provide insight into how a single neuromodulatory circuit can exert flexible, context-dependent control over diverse social and non-social behaviors.
To further probe the hypothalamic networks controlling appetite, I have utilized whole-brain activity mapping to identify hypothalamic neural populations encoding hunger and satiety. My results indicate that, similar to mammals, medial and lateral regions of the hypothalamus show anti-correlated activity patterns, which likely regulate distinct phases of appetite. In hungry fish, medial hypothalamic nuclei report an energy deficit, whereas more lateral regions may be involved in voracious eating. I demonstrate that one medial hypothalamic population, the serotonergic caudal periventricular hypothalamus, is an important regulator of lateral hypothalamic (LH) activity and food intake, and a separate serotonergic population, the superior raphe nucleus, is important for regulating food intake during satiety, also via the LH, but is dispensable during hunger. Thus, by dissecting serotonin circuit function in the context of other hypothalamic feeding networks, I show how a single neuromodulator can control food intake in a satiation state-dependent manner. Overall, these studies provide insights into the underlying evolutionary principles and logic governing hypothalamic function, and demonstrate how diverse neuromodulatory circuits in the hypothalamus and beyond can exert state-dependent control over an animal’s most primitive, yet essential, survival drives.Biology, Molecular and Cellular
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Venugopalan, Viswanath. "Compulsion and control: prefrontal and mesolimbic systems in human addiction". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103490.
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Introduction: Addiction to drugs is a chronic disorder characterized by loss of control over substance use despite adverse personal consequences. Addiction can be conceived as the point where drug use is no longer under volitional control and, becomes characterized by compulsive seeking and taking. Drugs of abuse are believed to target two systems thought to be critical for adaptive behaviour, 1) a goal-oriented system relying on prefrontal cortex activity to exert control over behaviour and 2) a motivation system supported by mesocorticolimbic dopamine transmission. These systems are thought to be subverted in addiction. Interestingly, there is a subset of long-term drug users, 'chippers', who, despite considerable exposure to drug, do not manifest the hallmark loss of control or exaggerated drive for drugs that typifies addicted users. To better understand whether prefrontal function, motivation or both distinguish 'chippers' from addicted individuals, we conducted the follwing experiments. Methods: We first examined the effects of lowering dopamine synthesis on motivation to smoke both nicotine-containing and denicotinized cigarettes in three groups of smokers: (i) low-frequency smokers who have smoked for no more than a year, (ii) low-frequency smokers who have stabilized at this level for at least 3 years, and (iii) high-frequency smokers. Next we used a neurocognitive battery testing regional aspects of prefrontal function in low- vs. high-frequency smokers while sated and following an 18 h abstinence period. Finally we examined the effects of lowering dopamine synthesis on regional prefrontal function. Results: 1) All smokers worked for more nicotine-containing cigarettes than de-nicotinized ones. 2) High-frequency smokers worked for more nicotine-containing cigarettes compared to low-frequency smokers. 3) Lowering dopamine synthesis reduced the self-administration of nicotine-containing cigarettes in all three smoker groups and did so without influencing conscious craving or pleasure. 4) Low-frequency smokers were better than high-frequency smokers at inhibiting an on-going motor response indicated by lower stop signal reaction time, consistent with dysfunction in lateral or dorsomedial prefrontal cortex. 5) Overall, lowering dopamine synthesis did not affect executive function. However, post-hoc analyses revealed that the personality trait of novelty seeking, a hypothesized proxy for baseline dopamine function, predicted changes in executive function subsequent to lowered dopamine synthesis. Using this approach, we discovered that lowering dopamine synthesis altered attentional biases to smoking cues as measured by the smoking Stroop in a pattern consistent with an inverted 'U' relationship between dopamine and performance. Conclusion: These data suggest the following. i) Dopamine transmission is involved in the motivation to smoke nicotine-containing cigarettes, and this role persists across stages of tobacco use and addiction. ii) Response inhibition mediated by dorso-medial prefrontal cortex and right inferior frontal gyrus distinguishes low- from high-frequency smokers. This group difference might influence the ability to restrict smoking, and protect low-frequency smokers from addiction. iii) No group-wise differences in prefrontal function were observed following reduction of dopamine synthesis. However, post-hoc analyses revealed that the personality trait of novelty-seeking, used as a proxy for baseline dopamine reactivity, predicted the effect of reduced dopamine synthesis on a task measuring attention to smoking cues according to an inverted 'U' function. Together, these studies add to our understanding of the role of dopamine in maintaining motivation to obtain nicotine-containing cigarettes, the neurobiological differences between low- and high-frequency smokers and the role of individual differences in personality traits in predicting the effects of dopamine manipulation on task performance.Introduction : La toxicomanie est un trouble complexe, chronique et qui revient, caractérisée par une perte de contrôle sur la consommation de drogues malgré la menace très réelle de se faire du mal. C'est le point où l'utilisation de drogues n'est plus volontaire mais caractérisée par la recherche et prise de drogues compulsives. La transition à la toxicomanie serait le résultat de changements à des circuits neuronaux induits par la drogue. Le système de la dopamine (DA) méso-cortico-limbique est impliqué dans le motivation, le renforcement et la modulation du contrôle exécutif et le cortex préfrontral (CPF) est impliqué dans le contrôle exécutif. Durant la progression à la toxicomanie, des adaptations à ces systèmes 1) érodent la capacité de résister à la prise de drogues, et 2) exagèrent la saillance encourageante de la drogue et des stimuli associés aux drogues. Ce qui est intéressant c'est que l'exposition à la drogue ne mène pas nécessairement à la toxicomanie. Un sous-ensemble de consommateurs de drogues, les « chippers », ne manifestent pas la perte de contrôle typifiant les toxicomanes. Qu'est-ce qui protège ces gens contre la toxicomanie? Ce qui est remarquable c'est que les différences neurobiologiques des circuits neuraux de la motivation et du contrôle qui distinguent les toxicomanes des chippers n'ont pas encore été étudiées de manière systématique. Méthodes : Nous avons mesuré l'effet d'une manipulation de la DA sur la motivation de fumer et le biais de l'attention vers les stimuli associés à l'action de fumer et sur les tâches qui jaugent la fonction exécutive, contrôlée par le CPF, chez (i) les fumeurs à basse fréquence qui fument depuis un maximum de un an (FBF), (ii) les fumeurs à basse fréquence qui se sont stabilisés à ce niveau pour au moins trois ans (FBFS), et (iii) les fumeurs à haute fréquence stables (FHF). Les résultats principaux sont les suivants. Résultats: 1) Baisser la synthèse de la DA a diminué la consommation de cigarettes contenant de la nicotine chez les 3 groupes de fumeurs mais n'a pas eu d'effet sur le goût conscient ou le plaisir de fumer. 2) Tous les fumeurs ont travaillé plus pour des cigarettes contenant de la nicotine que pour celles qui n'en contenaient pas. 3) Les FHF ont aussi plus travaillé pour les cigarettes avec nicotine que les FBF et FBFS. 4) Les FBF/FBFS étaient meilleurs que les FHF à une tâche consistant d'empêcher une réponse motrice en cours, jaugée par le temps de réaction suivant un signal d'arrêt, un modèle de déficience déjà observé chez les patients avec des lésions focales au CPF latéral et dorso-médial. 5) En général, la déplétion aigue de phénylalanine et tyrosine (DAPT) n'a pas eu d'effet sur la fonction exécutive (FE). Par contre, des analyses post-hoc ont démontré que la recherche de la nouveauté (RN), un index que l'on croit représenter la fonction DA de base, prédisait les changements à la FE induite par la DAPT. En utilisant cette approche, nous avons découvert qu'en accordance avec une fonction « U » inversée, la DAPT modifie les biais de l'attention vers les stimuli associés à l'action de fumer, mesurés par le Stroop de la cigarette. Conclusion: En résumé, l'inhibition de réponses contrôlées par un réseau du CPF dorso-médial/gyrus inférieur droit, distingue les chippers de tabac des FHF. Ceci peut être perçu comme étant un facteur clé contribuant à la capacité de restreindre son habitude de fumer, protégeant ainsi les chippers de tabac contre la progression à la dépendance aux drogues. Nous présentons donc de nouvelles données qui ajoutent à notre compréhension des différences neurobiologiques qui séparent les fumeurs à basse et haute fréquence, et du rôle de la DA dans le maintien de la motivation d'obtenir des cigarettes avec nicotine. Ces données pourraient être utiles pour concevoir des interventions mieux ciblées pour les fumeurs.
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Jayaraman, Divya. "The role of centriole biogenesis in control of brain size". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845435.
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Mutations in several genes that encode centrosomal proteins dramatically decrease the size of the human brain, which is the largest in the primate lineage, but how the proteins encoded by these microcephaly (‘small brain’) genes interact in a cellular process is poorly understood. The centrosome is the main microtubule-nucleating organelle in animal cells and consists of two centrioles, which duplicate once per cell cycle. Asymmetric inheritance of centrosomes may be critical to the maintenance of stem cells but the mechanism is controversial. In this dissertation, I characterize the functions of ASPM and WDR62, the two most common genetic causes of primary microcephaly, in centriole biogenesis and neocortical development, using in vivo loss-of-function studies in the mouse, combined with biochemical and cell biological approaches.
Here, I show that WDR62 and ASPM encode proteins that localize to the mother centriole, interact physically, control a common cellular function, and interact genetically to control brain size in mice. Whereas mice lacking either Wdr62 or Aspm are microcephalic but viable, mice lacking both are embryonically lethal, and heterozygous mutation in either gene enhances the phenotype of mutations in the other, suggesting a genetic interaction between Wdr62 and Aspm. Mass spectrometry analysis of the WDR62 interactome identified ASPM as a binding partner of WDR62, which was confirmed by co-immunoprecipitation. Mouse embryonic fibroblasts (MEFs) deficient in Wdr62, Aspm or both show similar defects in centriole duplication, with the severity of the cellular defect proportional to the severity of the microcephaly. This defect in centriole duplication was also confirmed in situ in the developing mouse brain by crossbreeding with a GFP-Centrin reporter line. WDR62 is required for centrosomal localization of ASPM and other microcephaly-associated proteins. Loss of Wdr62 causes a reduction in centrosomes and cilia, as well as a premature dissociation of ciliary membrane remnants from centrosomes during neurogenesis, resulting in a precocious generation of basal progenitors at the expense of apical progenitors.
Together, these results reveal previously unknown functions of, and interactions between, WDR62 and ASPM in centriole biogenesis and neocortical development. Microcephaly genes may thus cooperate in ensuring centriole duplication, maintaining adequate numbers of centrosomes, cilia and apical progenitors during neurogenesis, and regulating brain size.Medical Sciences
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Keen, Douglas Andrew. "Neural and muscular control of the human extensor digitorum muscle". Diss., The University of Arizona, 2002. http://hdl.handle.net/10150/280191.
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The human hand has incredible dexterity which depends, in large part, on the ability to move the fingers relatively independently. Interestingly, many of the primary finger flexor and extensor muscles possess a single belly that gives rise distally to multiple tendons that insert onto all the fingers and consequently might produce movement in all of the fingers. Therefore, the objective of this dissertation was to examine the neuromuscular organization of a multi-tendoned finger extensor muscle, the human extensor digitorum (ED). Initially, we found that ED spike-triggered average motor unit force was broadly distributed across the digits. Consequently, we hypothesized that linkages between the distal tendons of ED may cause force developed in a single compartment to be transmitted to neighboring tendons. However, force arising from intramuscular stimulation was fairly focused to a single digit suggesting that inter-tendonous connections account for little of the broad distribution of motor unit force. An alternative possibility was that our spike-triggered averages of motor unit force were contaminated by correlated activity among motor units residing in different compartments. Strong motor unit synchrony was found for motor unit pairs within compartments and a modest degree of synchrony for motor unit pairs in neighboring compartments which likely contributed to the appearance of spike-triggered average motor unit force on multiple fingers. These results suggest that last-order synaptic projections appear to supply predominantly sub-sets of motor neurons innervating specific finger compartments of ED but also branch to supply motor neurons innervating other compartments. Finally, single motor axons branch to innervate muscle fibers situated in multiple compartments of ED. Interestingly, force resulting from intraneural micro stimulation of single motor axons innervating ED was highly focused to a single digit. Therefore, it appears that the muscle fibers innervated by a motor axon are primarily confined to one of four distinct compartments of ED. Based on these experiments we believe that each finger is acted upon by ED through a discreet population of motor units. Consequently, extension of an individual finger would require the selective activation of motor neurons innervating a specific compartment of ED.
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Lee, Andrew Moses. "Neural circuit for locomotor control, brain state modulation, and decision-making". Thesis, University of California, San Francisco, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3599392.
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Locomotion is a behavior essential for survival. It is important for guiding goal-directed approach towards desired outcomes and avoidance of aversive stimuli. To this end, a large number of processes in the brain are both regulated by and serve to inform the locomotor behavior of animals. Here, we attempt to define the neural circuits underlying locomotor control, the associated changes that locomotion has upon brain states, and the neurobiological basis of locomotor decisions. In Chapter 1, we describe what is known regarding the neural circuits guiding locomotor behaviors. We provide background also regarding the known mechanisms that guide changes in brain states and are associated with locomotion. We then touch upon recent literature attempting to understand how information is used to guide decision-making to better understand the specific problem of how locomotor decisions are made. In Chapter 2, we then present novel findings, identifying brainstem circuits that control locomotion and concurrently regulate visual processing of information in the cortex through the basal forebrain. These findings may apply to other networks beyond the visual system and form a general mechanism by which various brain regions are modulated by behavioral state. In Chapter 3, we demonstrate that these brainstem circuits are under the regulation of the basal ganglia. These studies identify a conserved, phylogenetically ancient pathway for guiding locomotion that may exist in all vertebrates and represent one of the earliest functions of the basal ganglia system. In chapter 4, we leverage our understanding of the basal ganglia pathways for locomotor control to understand the processes of goal-directed decision-making. In chapter 5, we find that the ventral striatal shares a parallel organization to the dorsal striatum for implementing reinforcement learning to guide future locomotor decision-making. These studies into the basis of goal-directed locomotor behaviors may elucidate general principles for decision-making. Collectively, these results demonstrate control systems for locomotion are deeply interconnected with a diverse array of processes throughout the brain that guide goal-directed locomotor behaviors.
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Johnson, Otto Luke Ross. "Physiological and anatomical control of burst firing in the substantia nigra". Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268205.
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Murphy, Alexander James. "RNA and Protein Networks That Locally Control Brain Wiring During Development". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467385.
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The molecular machineries of growth cones control the formation of neural circuits in the developing brain. Although great progress has been made in elucidating axon guidance cues and their growth cone receptors, we still lack an understanding of the projection-specific RNA and protein networks in growth cones that likely control the wiring of specific circuits in vivo.
To understand how specific projection neurons make wiring decisions, I focus on callosal projection neurons (CPN), which connect the two cerebral hemispheres through the corpus callosum. I developed an approach to profile and quantify the full-depth transcriptomes and proteomes of CPN growth cones and their parent cell bodies isolated in vivo. Using this comparative approach, I uncover general patterns of RNA and protein subcellular localization, with several previously unrecognized features, that might control the wiring of specific brain circuits. First, while most transcripts are expressed at similar levels in cell bodies and growth cones, a select subset are more than 10-fold enriched in growth cones compared to cell bodies, indicating active localization of those transcripts to the growth cone. By then correlating transcriptomic and proteomic data, I characterize the spatial relationship between coding transcripts and their encoded proteins. Intriguingly, many of the growth cone-enriched transcripts are noncoding RNA with unknown function. Further, growth cones appear to have distinct ribosomes. These ribosomes lack several large subunit proteins, raising the intriguing possibility of growth cone-specific translational mechanisms for selective mRNA expression.
This approach is readily adaptable to other projection types in the brain, enabling high-throughput, quantitative investigation of RNA and protein controls over circuit development and, potentially, the regeneration of damaged circuitry. In addition, the approach is scalable to include epigenetic profiling, enabling full investigation of DNA, RNA, and protein networks that collectively coordinate brain wiring during development. The insights derived from this approach exemplify its capacity to quantify and characterize the molecular and translational mechanisms that control specific brain wiring at the subcellular level in vivo.Medical Sciences
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Milstein, Aaron D. "Control of excitatory synaptic strength by auxiliary subunits of AMPA receptors". Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3359580.
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Hu, Wen Fan. "Building a Bigger Brain: Centriole Control of Cerebral Cortical Development". Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070046.
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Human genetics has identified essential roles for many centriole- and cilia-related proteins during human development. Mutations in centrosome-associated genes commonly cause microcephaly, or "small brain," and mutations in cilia-associated genes cause a diverse spectrum of diseases termed "ciliopathies." However, the functional relationships between these two crucial organelles are less well studied.
The activities of centrosome-related proteins during mitosis and cytoskeletal remodeling are well-characterized, but their in vivo functions are incompletely understood. Here, we identify novel human mutations in a centrosomal gene which encodes a regulatory subunit of a microtubule interacting protein, and uncover unexpected pathways during vertebrate development. Human mutations cause severe microlissencephaly, reflecting defects in cerebral cortical neurogenesis, and loss of function in mice and zebrafish confirm essential roles in embryonic development, neurogenesis, and cell survival. Surprisingly, null mutant embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. Deficient induced pluripotent stem cells and lymphoblasts show defective proliferation and spindle structure, while deficient fibroblasts also demonstrate a remarkable excess of centrioles, including excessive maternal centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal novel roles for this protein in regulating overall centriole number, mother centriole and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.
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Van, Horn Marion. "Vergence eye movements redefined: the neural control of fast versus slow vergence". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96671.
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Seeing in 3D relies on the fact that our two eyes are spaced slightly apart. As a result, when our eyes are aligned on an object each eye has its own, slightly different view of the world. Information about relative depth is sent from visual cortex to the motor control centers in the brainstem, which are responsible for generating appropriate motor commands to move the eyes. Surprisingly, how the neurons in the brainstem use the depth information supplied by visual cortex to precisely aim each eye on a visual target remains highly controversial. This thesis investigates how individual neurons control the movement of each eye when we look between objects located at different depths. I first studied the signals encoded by individual oculomotoneurons during conjugate and disconjugate saccades and evaluated the role the antagonist muscle plays in accurate binocular positioning. I found that a first-order model (containing eye position and velocity terms) provided an adequate description of the neural discharges of oculomotoneurons during conjugate saccades. However, during disconjugate saccades I found the conjugate sensitivities could not be used to predict the responses during disconjugate saccades. Instead, the majority of the neurons preferentially encoded the movement of the ipsilateral eye. I next studied the signals carried by saccadic burst neurons during conjugate and disconjugate saccades. I first showed that the majority of the saccadic burst neurons dynamically encode the movement of the ipsilateral eye during the fast saccadic component of a movement. Moreover, using a neural simulation I found that the saccadic burst generator carries all the vergence drive necessary to shape the activity of the abducens motoneurons to which it projects. These results are consistent with the proposal that classically assumed "conjugate" saccadic structures in the oculomotor brainstem underlie vergence facilitation by providing monocular saccadic commands to the abducens during disconjugate saccades and a separate vergence pathway is used to adjust ocular alignment following the saccadic component of the movement. Subsequently, I tested the prediction that if the monocular commands issued by saccadic burst neurons are important for facilitating vergence velocities during horizontal saccades, they should also contribute to facilitating vergence associated with a vertical saccade when the conjugate component of the movement is negligible. As predicted, I found that saccadic burst neurons are also well suited for facilitating vergence during vertical saccadic movements. In particular, saccadic burst neurons contribute to generating increased vergence velocities by dynamically encoding the movement of an individual eye rather than the conjugate component of the movement.Finally, I used single unit recording and microstimulation techniques to investigate the role the superior colliculus plays in generating vergence eye movements. I provide evidence that individual neurons within the rostral SC encode slow changes in vergence angle. These results suggest that there exists a distinct grouping of neurons that encode slow vergence within the rostral SC and indicate that activation of the rostral SC underlies the ability to accurately position each of the two eyes when fixating targets in 3-dimensional space to ensure stereopsis.Taken together, my findings provide important new insight into how the brain controls 3-dimensional gaze shifts. I provide evidence that distinct neural pathways control fast and slow vergence. These results contradict the traditional view that the brain is circuited with independent pathways for conjugate and vergence control and suggest the need to update textbooks and review articles to emphasize the physiological differences between the neural circuitry controlling fast and slow vergence.Voir en 3D se fonde sur le fait que nos deux yeux sont espacés légèrement l'un de l'autre. En conséquence, chaque œil a sa propre vision différente du monde lorsque nos yeux s'alignent sur un objet. L'information recueillie sur la profondeur relative est envoyé du cortex visuel aux centres moteurs du tronc cérébral qui sont responsables des commandes motrices appropriées pour le mouvement des yeux. Cependant, la manière avec laquelle les neurones du tronc cérébral emploient l'information de profondeur fournie par le cortex visuel pour viser chaque œil sur un objectif visuel avec précision reste fortement controversée. Cette thèse étudie comment les différents neurones commandent le mouvement de chaque œil lorsque nous regardons des objets localisés à profondeurs différentes.Pour commencer, j'ai étudié les signaux produits par différents neurones oculomoteurs lors des saccades conjuguées et disconjuguées et j'ai évalué le rôle des muscles antagonistes sur la précision du positionnement binoculaire. J'ai constaté que le modèle de premier ordre décrit adéquatement les décharges neuronales des neurones oculomoteurs lors des saccades conjuguées. Cependant, j'ai trouvé que les sensibilités conjuguées ne peuvent pas être employées pour prévoir les réponses des saccades disconjuguées lors de ces dernières. Au lieu de cela, la majorité des neurones préfèrent le codage de la direction de mouvement de l'œil ipsilatéral. Par la suite, j'ai étudié les signaux portés par les neurones phasiques lors des saccades conjuguées et disconjuguées. J'ai montré que la majorité des neurones phasiques codent dynamiquement le mouvement de l'œil ipsilatéral. En plus, j'ai constaté que le générateur de la saccade déchargeant en bouffée porte toute la commande de vergence nécessaire pour former l'activité des neurones moteurs de l'abducens auxquels ils projettent. Ces résultats correspondent au modèle qui a classiquement supposé que les structures de saccades « conjuguées » du tronc cérébral oculomoteur sont à la base de la facilitation de vergence en fournissant les commandes monoculaires de saccades aux noyaux d'abducens lors des saccades, alors qu'une voie séparée est employée pour l'ajustement de l'alignement oculaire suite aux composantes saccadiques du mouvement. Par la suite, j'ai examiné la prévision qui si les commandes monoculaires initiées par les neurones phasiques sont importantes pour faciliter les vitesses de vergence lors des saccades horizontaux, alors qu'ils devraient également contribuer à faciliter la vergence lié aux saccades verticales lorsque les composantes conjuguées du mouvement sont négligeables. J'ai constaté que les neurones phasiques sont également bien adaptés pour faciliter la vergence pendant les mouvements oculaire de saccades verticales. En dernier, j'ai employé la configuration d'électrode simple pour l'enregistrement et des techniques de microstimulations pour étudier le rôle du colliculus supérieur (SC) dans les mouvements oculaires de vergence. J'ai fourni l'évidence que les différents neurones dans le SC rostral codent pour les changements d'angle de vergence. Ces résultats suggèrent qu'il existe au niveau du SC rostral, un groupe de neurones qui encodent les mouvements de vergence lent. L'activation du SC rostral montre la capacité à positionner précisément chacun des yeux lors d'une fixation de cible dans l'espace en 3-dimensions dans le but d'assurer la stéréoscopie. Dans l'ensemble, je démontre qu'il existe des circuits neuronaux distinctifs pour le contrôle des mouvements de vergence rapides et lents. Ces résultats sont contradictoires avec la vision traditionnelle du cablage du cerveau avec des réseaux indépendants pour le contrôle des mouvements conjugués et de vergence.
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Hennessy, Morgan Lorraine. "Function-Specific Serotonergic Neurons in the Control of Breathing and Body Temperature". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845412.
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The control of respiration and body temperature involves neural circuits within the brainstem modulated by the neurotransmitter serotonin (5HT), though it is unclear precisely which serotonergic neurons are critical to these functions. Recent work from our laboratory and others has demonstrated considerable heterogeneity among serotonergic neurons – in their projection targets, expressed genes, and developmental origin – which we hypothesize reflects the subserving of distinct functions by distinct serotonergic neuron subtypes. More specifically, our laboratory has parsed molecular subtypes of serotonergic neurons by their co-expression of the pan-serotonergic gene Pet1 along with a marker gene. When partnered with intersectional genetic tools, selective access to each subtype for functional study is enabled. Through application of these tools, we have identified a subtype of serotonergic neuron, designated the Egr2-Pet1 subtype, which modulates the CO2 breathing reflex and projects to CO2 chemosensory brain centers. Here, we describe a new molecular subtype of serotonergic neuron, defined by Tachykinin 1 (Tac1) expression, that projects to respiratory motor nuclei. Upon silencing the Tac1-Pet1 subtype, we show that it, too, modulates the CO2 breathing reflex, but presumably by affecting respiratory motor output. Thus, two discrete subtypes of serotonergic neurons modulate breathing: one involved in sensory processing and the other involved in motor output, reflecting an unexpected division of serotonergic labor along the motor-sensory axis. In parallel, we tested the contribution of serotonergic neuron subtypes to body temperature modulation, as we have previously shown that en masse acute silencing of serotonergic neurons leads to hypothermia. We provide evidence that serotonergic neurons within the median raphe and raphe pallidus may contribute to this task. In these studies, we manipulated serotonergic neuron activity via hM4Di-mediated hyperpolarization using the intersectional allele RC::FPDi, for which parameters were optimized and defined. In summary, we have identified molecularly and functionally distinct subtypes of serotonergic neurons necessary for normal homeostatic regulation. Results may shed light on homeostatic disorders involving 5HT, such as sleep apnea and sudden infant death syndrome, as well as inform strategies for potentially minimizing homeostatic side effects of present 5HT-affecting therapeutics.Medical Sciences
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Choe, Katrina. "Effect of chronic hypernatremia on osmoreceptor and baroreceptor control of supraoptic neurons". Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119478.
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High consumption of dietary salt is prevalent in our society today and has been linked to pathologies such as salt-sensitive hypertension. The mechanism by which high salt causes increases in blood pressure remains unclear. Vasopressin (VP) is a neurohypophyseal hormone proposed to be involved in the etiology of salt-sensitive hypertension, because (i) high plasma sodium following dietary salt consumption triggers its release and (ii) a sufficiently high circulating concentration of the hormone can cause vasoconstriction. Two factors have been identified to have a major inhibitory influence over VP release – hypoosmolality and baroreceptor activity. Taurine release from astrocytes triggered by hypoosmolality is thought to mediate an inhibitory tone on glycine receptors (GlyRs) present extrasynaptically in VP neurons, and presynaptic GABA release triggered by baroreceptor activation has been well-established to synaptically inhibit the activity of VP neurons via GABAA receptors. In rats, chronic hyperosmolality induces concurrent rises in plasma sodium and blood pressure. Interestingly, this condition is reported to cause several alterations in the supraoptic nuclei (SON) housing VP neurons, which may have a profound impact on the inhibitory mechanisms of these neurons. First, a collapse in the chloride gradient of SON neurons is observed during chronic hyperosmolality, potentially abolishing both GlyR- and GABAA receptor-mediated inhibitory inputs known to rely on the ionic gradient. Second, it is well-established that chronic hyperosmolality induces a retraction of astrocytic processes away from neurons in the SON, possibly removing all forms of communications between these two cell types including the hypothesized taurine-mediated GlyR tone. In this thesis, we tested the hypothesis that both types of inhibition in the SON are abolished as a result of these chronic hypernatremia-related changes, and the resulting lack of inhibition may contribute to a hyperexcitation of SON neurons and a consequent VP-mediated increase in blood pressure. We first present what we believe is conclusive evidence proving that taurine release from astrocytes is responsible for the hypoosmolality-sensitive GlyR tone on VP neurons, and further demonstrate the disappearance of this inhibition after chronic hypernatremia. We next demonstrate the effect of chronic hypernatremia on the morphology of SON astrocytes and how it impacts their physical and functional interactions with VP neurons. We then show that baroreceptor inhibition of VP neurons is also abolished under these conditions due to a collapse in the chloride gradient of these neurons. Finally, we show that the resulting removal of inhibition from both synaptic and glial sources contribute to increased excitability of VP neurons and thus induces a high level of circulating VP, which triggers systemic vasoconstriction and elevates blood pressure. In conclusion, we offer a central mechanism in which VP may contribute to the development and maintenance of salt-sensitive hypertension and raise its possibility as a potential treatment target.La consommation excessive de sel alimentaire est un phénomène répandu dans notre société et elle mène à plusieurs pathologies telles que l'hypertension sensible au sel. Le mécanisme par lequel une forte teneur en sel entraîne une augmentation de la pression artérielle demeure incertain. La vasopressine (VP) est une hormone neurohypophysaire que l'on croit être impliquée dans l'étiologie de l'hypertension sensible au sel. En effet, suite à une consommation de sel, il y a une augmentation de sodium plasmatique qui déclenche l'excrétion endocrine de VP et qu'une concentration suffisamment élevée de cette hormone dans le plasma sanguin peut provoquer une vasoconstriction. La libération de VP est inhibée par hypoosmolalité et l'activité des barorécepteurs. Dans les neurones VP, l'activité basale inhibitrice et hypoosmo-sensible médiée par les récepteurs de la glycine (GlyRs) extrasynaptiques est supposée provenir de la taurine qui est libérée par les astrocytes avoisinants. De plus, le rôle des récepteurs GABAA a été bien établi pour l'inhibition des neurones VP par les barorécepteurs. Chez le rat, le traitement hyperosmotique chronique induit à la fois une hausse de sodium plasmatique et de la pression artérielle. Fait intéressant, ce traitement conduit à deux modifications dans les noyaux supra-optiques (SON) contenant ces neurones VP, qui peuvent profondément influer sur les mécanismes inhibiteurs de ces neurones. Tout d'abord, il y a un atténuation du gradient du chlore dans ces neurones, qui peut conséquemment inhiber les deux mécanismes qui s'appuient sur des canaux perméables au chlore. Deuxièmement, les astrocytes rétractent leur processus loin des neurones du SON, supprimant ainsi toutes communications entre ces deux types de cellules, y compris l'hypothèse concernant l'activité basale des GlyR médiée par la taurine. Dans cette thèse, nous avons testé l'hypothèse que ces deux types d'inhibition dans le SON sont abolis à la suite de ces deux changements induit par l'hypernatrémie chronique, et que l'absence d'inhibition qui en résulte peut contribuer à une hyperexcitation des neurones du SON et donc à une augmentation de la pression artérielle médiée par la VP. Nous démontrons tout d'abord que la libération de taurine à partir d'astrocytes est responsable de l'activité basale inhibitrice et hypoosmo-sensible médiée par les GlyRs sur les neurones VP et qu'il y a une disparition de cette inhibition après une hypernatrémie chronique. Nous démontrons ensuite l'impact de cette condition sur la morphologie des astrocytes et de leurs interactions avec les neurones VP. Nous démontrons ensuite que l'effet inhibiteur des barorécepteurs sur les neurones VP est également supprimé en raison de l'atténuation du gradient de chlore dans ces neurones. Enfin, nous montrons que la perte d'inhibition par les sources synaptiques et gliales, contribue à augmenter l'excitabilité des neurones VP, ce qui se traduit par une augmentation de la pression artérielle médiée en partie par une vasoconstriction systémique induite par la VP. En conclusion, nous proposons un mécanisme central dans lequel la VP peut contribuer au développement et au maintien de l'hypertension sensible au sel et à considérer sa possibilité comme une cible thérapeutique potentielle.
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Hunt, Alexander Jacob. "Neurologically Based Control for Quadruped Walking". Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1445947104.
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McLachlan, Ian Gordon. "Genetic control of dendrite morphogenesis in C. elegans". Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493511.
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The shapes and attachments of cells determine the machinery of organs; for example, the shapes and attachments of neurons and glia establish the wiring of the brain. To understand how neuronal dendrites obtain their morphologies and make the appropriate connections, we used C. elegans sense organs as models. Previous work identified a requirement for the extracellular matrix protein DYF-7 in dendrite extension: DYF-7 anchors dendrites dendrite endings at the embryonic nose while neuronal cell bodies migrate away, and in its absence, dendrites fail to extend. Here, we show that these dendrites are part of a sensory epithelium composed of glial cells and neurons. The dendrites are ensheathed by glial cells, form adherens junctions onto glia, and are stabilized at their apical surfaces by the extracellular matrix protein DYF-7. In dyf-7 mutants, the pulling force of cell migration causes this sensory epithelium to rupture along the glia:glia junctions. By comparison, dendrites of the URX and BAG neurons are intimately connected to the external surface of glial cells but are not known to form adherens junctions and are not affected in dyf-7 mutants. To identify factors required for URX and BAG dendrite extension, we performed forward genetic screens for dendrite extension defects in these cells and identified mutations in the cytoplasmic protein GRDN-1/Girdin and the adhesion molecule SAX-7/L1CAM. We show that in wild-type embryos, URX and BAG dendrites also extend by attaching to the nose and then stretching during embryo elongation but, in grdn-1 embryos, they fail to remain attached. GRDN-1 can promote dendrite attachment by acting in glia—it localizes to glial endings and causes localized accumulation of SAX-7, creating an adhesive compartment where dendrites attach. Thus, GRDN-1 and SAX-7 determine dendrite length by positioning a neuron-glia attachment site that couples dendrite extension to embryonic growth. Finally, we identified several other mutants with URX dendrite morphogenesis defects, including overgrowth of the URX dendrite; some have been mapped to genes associated with the cytoskeleton. Together, these studies define genetic mechanisms that control morphogenesis of distinct classes of sensory dendrites through specific adhesive interactions with their glial neighbors.Medical Sciences
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Liu, Anita. "Brain regions involved in heading estimation and steering control in a virtual environment". Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=117133.
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The brain regions required for judging heading direction and actively steering towards a goal could be damaged by stroke. Identifying the neural correlates responsible for goal-directed locomotion is important for the understanding of the mechanism underlying neuroplasticity and functional recovery. Past research shows that when we are walking through a texture-rich environment, we primarily use optic flow, a radially expanding pattern of motion, to accurately discriminate our heading direction and steer towards a goal. The purpose of this study was to investigate the different brain regions involved in heading discrimination and steering using an ecological virtual environment, mimicking most environments we walk through in everyday life. Fourteen participants (7 males, 7 females) took part in an fMRI study where their BOLD responses were measured while they completed a heading discrimination and active steering tasks using a joystick. A cluster level inference was conducted and clusters that were statistically significant above a threshold of Z=4 (p<0.01) were identified. This study investigated which brain regions display higher BOLD responses in the heading discrimination and steering task, independent of motor movements from joystick input. Consistent with previous studies, the bilateral intraparietal sulcus is involved in heading discrimination and bilateral posterior cerebellum was observed in the steering task. Further analysis revealed that the hMT+ and V2, the bilateral cerebellum, supplementary eye fields, premotor cortex, and supplementary motor area, displayed higher BOLD responses in the steering task than in the heading discrimination task. These results suggest that although heading discrimination involves a certain degree of sensorimotor integration and optic flow processing, steering is a more demanding task, requiring more brain regions to transform dynamic optic flow information into context-adapted motor responses.L'indentification des régions du cerveau humain, requises pour juger la direction choisie et s'orienter activement vers notre but, pourrait aider à comprendre le fait que ceux qui ont eu un AVC ont des difficultés avec la locomotion orientée vers un but. Des études antérieures ont démontré que lorsque nous marchons dans un environnement avec des textures riches, nous utilisons principalement le flux optique, un modèle de mouvement d'expansion radiale, pour discerner avec précision la direction choisie et de se diriger vers une cible. Le but de cette étude était d'investiguer quelles régions du cerveau sont impliquées dans la discrimination et dans le contrôle de la direction (pilotage) en utilisant un environnement virtuel écologique qui ressemble à la plupart des environnements dans lesquels nous évoluons dans la vie quotidienne. Quatorze personnes (7 hommes, 7 femmes) ont participé à une étude de IRMf où leurs réponses BOLD ont été mesurées pendant qu'ils complétaient une tâche de discrimination et une tâche active de pilotage à l'aide d'une manette de commande, en réponse à des flux optiques de différentes directions. Une inférence de groupe a été réalisée et ceux statistiquement significatifs au-dessus d'un seuil de Z=4 (p<0.01) ont été identifiés. Cette étude portait sur les régions du cerveau qui ont affiché des réponses BOLD plus élevées dans les tâches de discrimination de la direction et de pilotage, indépendamment des réponses motrices associées aux mouvements de la manette de commande. Le sillon interpariétal (divisions antérieure et postérieure) a été impliqué bilatéralement dans la tâche de discrimination et une activation bilatérale du cervelet postérieur a été observée dans la tâche pilotage. D'autres analyses ont démontré que le complexe hMT+ et V2, des régions impliquées dans le traitement du flux optique, des régions bilatérales dans le cervelet, le cortex prémoteur et l'aire motrice supplémentaire présentaient des réponses BOLD plus élevées dans la tâche de pilotage que dans la tâche de discrimination. Ces résultats suggèrent que même si la discrimination de la direction implique un certain degré d'intégration sensorimotrice et de traitement du flux optique, le pilotage est une tâche plus exigeante nécessitant davantage de régions du cerveau pour transformer les informations dynamiques du flux optique en réponses motrices adaptées aux exigences contextuelles.
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Baker, Daniel Hart. "Interocular suppression and contrast gain control in human vision". Thesis, Aston University, 2008. http://publications.aston.ac.uk/1432/.
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The human visual system combines contrast information from the two eyes to produce a single cyclopean representation of the external world. This task requires both summation of congruent images and inhibition of incongruent images across the eyes. These processes were explored psychophysically using narrowband sinusoidal grating stimuli. Initial experiments focussed on binocular interactions within a single detecting mechanism, using contrast discrimination and contrast matching tasks. Consistent with previous findings, dichoptic presentation produced greater masking than monocular or binocular presentation. Four computational models were compared, two of which performed well on all data sets. Suppression between mechanisms was then investigated, using orthogonal and oblique stimuli. Two distinct suppressive pathways were identified, corresponding to monocular and dichoptic presentation. Both pathways impact prior to binocular summation of signals, and differ in their strengths, tuning, and response to adaptation, consistent with recent single-cell findings in cat. Strikingly, the magnitude of dichoptic masking was found to be spatiotemporally scale invariant, whereas monocular masking was dependent on stimulus speed. Interocular suppression was further explored using a novel manipulation, whereby stimuli were presented in dichoptic antiphase. Consistent with the predictions of a computational model, this produced weaker masking than in-phase presentation. This allowed the bandwidths of suppression to be measured without the complicating factor of additive combination of mask and test. Finally, contrast vision in strabismic amblyopia was investigated. Although amblyopes are generally believed to have impaired binocular vision, binocular summation was shown to be intact when stimuli were normalized for interocular sensitivity differences. An alternative account of amblyopia was developed, in which signals in the affected eye are subject to attenuation and additive noise prior to binocular combination.
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Melanson-Drapeau, Lysanne. "Connexin32-mediated control of progenitor cell fate in injured and uninjured adult mouse brain". Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/29364.
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Gap junction protein expression has been implicated in progenitor cell proliferation, survival, and specification during development. The present study was undertaken to establish the role of the gap junction protein connexin32 in dictating progenitor cell fate in adult mouse brain. In the dentate gyrus of the hippocampus, I localized the connexin32 protein to a subset of NG2 + early oligodendrocyte progenitors. In connexin32-null mutant mice, I found an increase in the total number of proliferating early oligodendrocyte progenitors and demonstrated that the turnover of these cells is constitutively enhanced (Chapter 2). Furthermore, behavioural testing in a learning and memory task revealed that connexin32-deficient mice exhibit impaired reference memory, indicating that progenitor cells may play a role in hippocampal associated cognitive function (Chapter 3). In vitro analysis further demonstrated that these progenitors are able to differentiate into neurons upon a neurogenic stimulus. In Chapter 4, I assessed the ability of hippocampal progenitors to activate and regenerate brain tissue in vivo, following kainic acid-induced epileptiform seizures, in the presence or absence of connexin32. I show that connexin32-null mutation promotes more effective neurogenesis from NG2+ progenitor cells activated in the CA3a/b pyramidal zone, following excitotoxic injury. To confirm the role of connexin32 in determining progenitor cell fate, I performed a series of gain of function studies by inducing ectopic connexin32 expression in neurosphere progenitor cultures (Chapter 5). I show that connexin32 promotes oligodendrogenesis in vitro, at the expense of neurogenesis. These experiments provide insight into connexin-mediated control of neural progenitor specification and begin to identify connexins as possible therapeutic targets following brain injury.
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Mooney, David M. "Cholinergic control of sensory synaptic transmission in primary and nonprimary auditory thalamus of rat". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ66175.pdf.
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Paré, Martin. "The neural control of fixation and saccadic gaze displacements by midbrain and brainstem structures". Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28880.
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Exploration of the visual world requires almost incessant movements of the visual axis (gaze), which are separated by periods of fixation. This thesis describes the neural control of fixation and saccadic gaze displacements. The superior colliculus (SC) is a mid-brain structure involved in gaze redirection executed either by the eyes alone or by combined eye and head movements. Microstimulation of the cat SC revealed a map of evoked gaze shifts, which was coextensive with the motor map encoded by the neuronal activity. The spatio-temporal characteristics of these evoked gaze shifts depended, to some extent, on stimulus parameters or active fixation. A definite role in fixation behavior for the fixation cells situated at the SC's rostral pole was revealed by showing that microstimulation of this area suppresses both electrically-evoked and natural gaze shifts. A pathway mediating this gaze shift suppression was demonstrated by physiological evidence that the SC's "fixation area" provides the major collicular input to brainstem omnipause neurons (OPNs), which inhibit the saccadic premotor elements. In the head-restrained animal, OPNs exhibit a pause in activity related to eye saccades. It was shown here that, in the head-unrestrained cat, OPNs pause not for the duration of rapid orienting eye movements, but for the entire duration of gaze shifts irrespective of the shape of the trajectory of the eye in the orbit. However, recording the OPNs during SC stimulation indicated that the pause is not directly related to the SC command, but to the movement overtly produced: either head-fixed eye saccades or head-free gaze shifts. We suggest that OPNs are controlled by two systems acting synergistically: a brainstem mechanism involved in quick phase generation and a collicular gaze saccade generator.
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Barbarosie, Michaela T. (Michaela Teodora). "Presynaptic control of 4-aminopyridine-induced activity in the in vitro adult rat hippocampus". Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22716.
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The convulsant and K$ sp+$ channel blocker, 4-aminopyridine (4AP), induces two types of synchronous, spontaneous field potentials in the stratum radiatum of the CA3 subfield, in an in vitro hippocampal slice obtained from adult rat. The first type of activity is a positive-going interictal-like potential that corresponds to a burst of population spikes, and is abolished by non-NMDA receptor antagonists; the second type of field potential is a low frequency, negative going synchronous event which is sensitive to GABA$ rm sb{A}$ receptor antagonism. Knowing that in the hippocampus, adenosine A1 receptors are located presynaptically, on the terminals of excitatory neurons, and that their activation prevents glutamate release, I have used a specific adenosine A1 receptor agonist and altered the occurrence of the interictal-like potential. It is also established that $ mu$ opioid receptors in the hippocampus are located presynaptically on GABAergic interneurons where their activation prevents release of GABA. Therefore, I have used a specific $ mu$ opioid receptor agonist and altered the occurrence of the negative-going field potential. In summary, the experiments reported in this thesis demonstrate that 4AP-induced activity is generated through a presynaptic mechanism at both excitatory (glutamatergic) and inhibitory (GABAergic) terminals. The relevance of this work is two fold: (i) it helps to better understand the mechanisms of 4AP-induced epileptogenesis and (ii) it highlights the putative role of adenosine as an antiepileptic drug.
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Khan, Rishi Lee. "Engineering systems neuroscience modeling of a key adaptive brain control system involved in hypertension /". Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 281 p, 2007. http://proquest.umi.com/pqdweb?did=1362523091&sid=21&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Dashti, Eman. "Role of receptor mediated endocytosis-8, a novel Parkinson's disease gene, in mitochondrial quality control". Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121496.
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Over the past two decades, significant understanding of the pathogenesis of Parkinson's disease (PD) has been attributed to the discovery of genes, that when mutated, are responsible for familial forms of PD. Recently a novel autosomal dominant mutation (AD) causing PD was identified in receptor-mediated endocytosis-8 (RME-8). When mutated, symptoms of PD manifest with an onset ~ 70 years of age. RME-8 is a DnaJ domain containing protein that plays an important role in intercellular trafficking and recycling of retrograde cargo. Loss of function of RME-8 disrupts the endosome to Golgi transport resulting in cargo accumulation in the endosome and its re-routing to the lysosome for degradation. Studies have shown that VPS35 (another AD-PD gene, and part of the retromer that RME-8 interacts with) is involved in the mitochondrial quality control pathway implicated in PD. In addition, recent studies have shown that bec-1, a protein long studied as a regulator of autophagy (part of the mitochondrial quality control pathway), to also be involved in the retrograde trafficking co-localizing with RME-8. These findings suggest a possible new role of RME-8 in the mitochondrial quality control pathway. Here we investigated the possible role of RME-8 in the mitochondrial quality control pathway implicated in PD. Using loss of function approach by knocking-down RME-8 and gain of function approach by overexpressing the mutant form of RME-8 we investigated its role in two pathways involved in mitochondrial quality control: mitophagy and mitochondrial vesicle formation. Our results show that RME-8 is not involved in either pathways and thus the exact role of RME-8 in the pathogenesis of PD has to still be elucidated.Des avancées significatives dans la compréhension de la pathologie propre à la maladie de Parkinson (MP) ont marqués les deux dernières décennies grâce, notamment, à la découverte de mutations génétiques responsables de formes familiales de la MP. Récemment, une mutation autosomale-dominante (AD) dans le gène RME-8 (receptor-mediated endocytosis-8) a été identifiée comme cause de la MP dont les manifestations cliniques associées à cette mutation apparaissent vers 70 ans. La protéine codée par RME-8, contient un domaine DnaJ qui joue un rôle important dans le trafic intracellulaire et le recyclage de cargos rétrogrades. La protéine RME-8 est exprimée dans plusieurs tissus et possède une forte affinité pour la chaperonne HSC70 (heat shock protein 70). RME-8 recrute HSC70 aux membranes couvertes de clathrine et interagit avec le complexe du retromère pour désassembler les triskelions de clathrine. La perte de fonction de RME-8 perturbe le transport de l'endosome au Golgi, ce qui entraîne l'accumulation du cargo dans l'endosome et sa redirection vers le lysosome. De plus, il a été démontré, que VPS35, fait partie du complexe du retromère et interagit avec RME-8, et que BEC-1 est impliquée dans le trafic rétrograde et que l'appauvrissement de RME-8 ou BEC-1 donne des phénotypes similaires. Puisque VPS35 et BEC1 jouent un rôle dans le contrôle de la qualité mitochnodriale, nous avons émis l'hypothèse que RME-8 est aussi impliquée dans ce processus. Ni l'ablation de RME-8 via l'ARN interférence ou sa surexpression n'a permis de montrer un rôle pour RME-8 dans la mitophagie ou la formation de vésicules mitochodriales. Nos données tendent à montrer que RME-8 n'est pas impliquées dans le contrôle de la qualité mitochondriale et que son rôle dans la pathogénèse de la MP demeure obscur.
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Richter, Franziska Rebekka. "The control of task sets and long-term memory". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:6537ad2c-107b-4517-8b37-7d5d59edbe3b.
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The current thesis explores the complex relationship between cognitive control and memory. A series of experiments combined task-switching paradigms with recognition memory tests to measure how switching between tasks influences effective control over long-term memory. In these experiments, participants were presented with compound stimuli consisting of a picture and an overlaid word, and were cued in each trial whether the word or the picture was relevant (attended) or irrelevant (unattended). Participants were then tested for their memory of items presented during task switching. Experiments 1-2 indicated that switching between tasks reduces the selectivity of processing: Switching was associated with impaired task performance as well as more similar memory ratings for attended and unattended items. Experiments 3-5 extended these findings by showing that enhanced top-down control positively affected task-performance as well as memory, in both cases by increasing the selectivity of processing toward task-relevant information. Experiments 6-7 replicated key effects with simple switches of visual attention, and explored the neural correlates of successful task performance and encoding using EEG. The key finding here was that previously observed ―subsequent memory‖ effects reflect, at least in part, selective encoding processes. The last chapter extended the focus of the investigation to explore the role of control in long-term memory retrieval. FMRI meta- analyses indicated considerable overlap in neural activation found during task switching and during the adoption of different retrieval sets. The results of Experiment 8 indicated that switching during task performance and later memory retrieval were both associated with decreased selectivity of processing. Collectively, the results of this thesis suggest that selectivity of processing is a critical factor in effective task performance and successful memory, with potentially very similar mechanisms underlying the two. This work demonstrates the fruitfulness of combining research on cognitive control and memory to study questions relevant for both fields.
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Hua, Silvia. "An examination of the effects of equilibrium on the control of goal-directed reaching in humans". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106579.
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Goal-directed reaching movements executed from seated positions exhibit rapid, automatic corrections in response to a change in target position. In the standing posture, corrections in arm trajectory during reaching movements are accompanied by feedforward corrections in postural activity which create the dynamical conditions necessary for successful task execution. However, it is unknown how equilibrium constraints associated with standing as opposed to sitting, which has little or no equilibrium constraints, influence the neural processes underlying online corrections of goal-directed movements. This thesis aimed to address this question. Eight healthy adult subjects (3 males, 5 females) performed regular reach-to-point movements and an online arm correction task when seated and when standing. It was hypothesized that the increased equilibrium constraints during stance would influence the online control of goal-directed reaching, resulting in differences in focal movement endpoint kinematics. The focal reaching movement was described using spatiotemporal kinematics of the reaching hand. Whole-body kinematic analyses were also performed to compare the movement strategies utilized in each postural configuration. It was found that the postural configuration (seated vs. standing) in which the movements were executed generally did not affect focal movement parameters (velocity profile, movement time, time to correction, and peak velocity), despite resulting in different whole-body kinematic strategies (i.e. extent of elbow flexion-extension, shoulder adduction-abduction, trunk rotation, pelvis rotation, pelvis obliquity, and pelvis translation). These results highlight the efficacy of the neural processes underlying the end goal of arm reaching movements and their online control. The processes of control do not appear to be affected by the higher demands placed on the CNS required for the maintenance of postural equilibrium during stance.En position assise, les mouvements de pointage sur une cible visuelle démontrent des corrections rapides et automatiques lors d'une perturbation spatiale de la cible. En position debout, des corrections posturales anticipent les corrections de la trajectoire de la main et créent les conditions dynamiques requises pour le déroulement du mouvement. Cependant, nous ne savons pas comment la position debout, qui pose plus de contraintes d'équilibre sur le mouvement que la position assise, affecte les processus neuraux à la base des corrections en ligne des mouvements de pointage. Le but de cette étude est d'aborder cette question. Les sujets (3 hommes, 5 femmes) ont pointé une cible visuelle en étant assis et en étant debout. Pour 33% des essais, la cible a été déplacée vers la droite sans prévenir le sujet, exigeant une correction en ligne du mouvement. La configuration posturale (assise/debout) n'a influencé ni la trajectoire de la main ni la correction en ligne du mouvement de la main, bien que les stratégies cinématiques du corps entier décrivant ces deux conditions posturales soient différentes. Ces résultats soulignent l'efficacité des processus neuraux à la base de mouvements de pointage et de contrôle en ligne; il semble que ces processus ne soient pas influencés par la demande neurale augmentée requise pour garder l'équilibre en restant debout.
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Jaiswal, Stuti J. "The Consequences of Developmental Nicotine Exposure on Neonatal Central Respiratory Control". Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/293608.
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Developmental nicotine exposure (DNE) exerts negative consequences on the CNS via the activation of nAChRs that are available early and widely throughout development (refs). In this work, we examined how DNE changed excitatory and inhibitory neurotransmission in brainstem regions involved in central breathing control. Previous work using the brainstem-spinal cord preparation had shown that DNE augmented the respiratory-related response to AMPA, muscimol (a GABAA agonist), and glycine (Luo et al., 2004; Luo et al., 2007; Pilarski and Fregosi, 2009a). These studies used a split-bath preparation in which a drug (AMPA, muscimol, or glycine) was applied to medulla, and the frequency of the respiratory response (in the form of spontaneous, rhythmic bursting activity) was recorded from cervical nerve 4 (C4), which provides output to the diaphragm. Although these studies showed that DNE AMPA, GABA(A), and glycine neurotransmission in the medulla, the regions mediating the effect and the mechanism of DNE's action remained unclear. In this study we tested the hypothesis that the observed changes in respiratory burst frequency were mediated through the preBötzinger complex (preBötC), and the mechanism of enhanced activity involved an upregulation of neurotransmitter receptors. Additionally, we were interested in studying the effect of DNE on breathing-related motor pools, and therefore studied DNE's effect on excitatory and inhibitory neurotransmission in the XIIMN. We approached these questions and aims using a combination of techniques, including extracellular recordings from whole nerve output in rhythmic brainstem slices, immunohistochemistry, and Western blotting. We found enhanced AMPA, GABA(A), and glycine neurotransmission in the XIIMN and preBötC, and varying changes in neurotransmitter receptor expression in both groups. Additionally, we found a decrease in motoneuron soma size in XII motoneurons that stained positively for the glycine receptor. Overall, this study shows that DNE alters inhibitory and excitatory neurotransmission in both the preBötC and XIIMN, and that these changes may be mediated through a combination of change in cell size and receptor expression.
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D'Alberto, Nicholas C. "Examining Inter- And Intra-Individual Differences In The Neurobiological Mechanisms Associated With Inhibitory Control". ScholarWorks @ UVM, 2018. https://scholarworks.uvm.edu/graddis/962.
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Adolescence is an ideal time to measure the development of the neural mechanisms associated with inhibitory control because this age period is marked by impulsive and risk taking behaviors. Maturational brain changes in the prefrontal cortex that are associated with the emergence of inhibitory control are thought to occur during this age. With knowledge of how this system develops, it may be possible to identify the development of disorders that arise from poor inhibitory control such as attention deficit hyperactivity disorder (ADHD) and substance use. The goal of the current dissertation is to examine the neurobiological correlates associated with individual differences in inhibitory ability, and examine the age-related changes in neurobiological mechanisms of inhibitory control. This report will be the first of its size (n = 538) to examine within-subject changes longitudinally over five years of adolescent development (age 14 to 19). Furthermore, we supplement the longitudinal data with findings from a split-brain patient on the lateralization of inhibitory control, and we explore a subtle nuance that may have large implications on how to best measure inhibition-related brain activity.
In the second chapter of the dissertation, we examine the lateralization of inhibitory control by measuring hemispheric differences in the ability to inhibit a motor response in a split-brain patient. Here, we found patient J.W.’s right hemisphere performed better than his left hemisphere on three different inhibitory control tasks. Interestingly, although inferior to the performance of the right hemisphere, the left hemisphere still performed relatively well on the three tasks, suggesting the left hemisphere can perform response inhibition independently.
The third chapter examines both the functional correlates of Stop Signal Task performance, and the age-related differences in the functional mechanisms of response inhibition. At age 14 and age 19, similar patterns of activation were associated with performance, however relatively little overall activity exhibited performance-related effects. Superior performance was associated with greater right inferior frontal gyrus (rIFG) activation, as well as greater activation in a set of regions potentially involved with a stimulus-detection and attention-orienting system. However, at age 14 performance was also negatively associated with default mode network activity, and at age 19 performance was also positively associated with left amygdala activity. In the absence of within-subject differences in performance between ages 14 to 19, there were significant decreases in functional activation associated with successful inhibition. The potential mechanisms by which activity decreases over time while performance remains stable are discussed.
The fourth chapter of the dissertation examines the effect of objective task difficulty on the magnitude of activation associated with successful inhibition. The Stop Signal Task employs an adaptive algorithm that alters task difficulty to meet participants’ abilities. Typically, when capturing functional activation associated with response inhibition, activation is extracted from all successful trials. Here, we find that individual differences in activation are expanded when using the activation from the extreme, rather than average, aspects of task performance variables. Individual differences in performance may best be captured by examining the maximum difficultly at which a participant is able to inhibit a response, rather than the average of all successful inhibitions. These results also lend support to the minimal activity associated with performance in Chapter 3, and we discuss how improving the measure of stop-related activity may help explain both inter- and intra-individual differences in inhibitory control.
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Keeler, Austin Byler. "Branching out by sticking together: elucidating mechanisms of gamma-protocadherin control of dendrite arborization". Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/2230.
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Growth of a properly complex dendrite arbor is a vital step in neuronal differentiation and a prerequisite for normal neural circuit formation; likewise, overly dense or sparse dendrite arbors are a key feature of abnormal neural circuit formation and characteristic of many neurodevelopmental disorders. Thus, identifying factors involved in aberrant dendrite complexity and therefore aberrant circuit formation, are necessary to understanding these disorders. In my doctoral work I have elucidated both intracellular and extracellular aspects to the gamma-protocadherins (γ-Pcdhs) that regulate dendrite complexity.
Loss of the 22 γ-Pcdhs, adhesion molecules that interact homophilically and are expressed combinatorially in neurons and astrocytes, leads to aberrantly high activity of focal adhesion kinase (FAK) and reduced dendrite complexity in cortical neurons. Little is known, however, about how γ-Pcdh function is regulated by other factors. Here I show that PKC phosphorylates a serine residue situated within the shared γ-Pcdh C-terminus; PKC phosphorylation disrupts the γ-Pcdhs’ inhibition of FAK. Additionally, γ-Pcdh phosphorylation or a phosphomimetic mutant reduce dendritic arbors, while blocking γ-Pcdh phosphorylation increases dendrite complexity. Together, these data identify a novel intracellular mechanism through which γ-Pcdh control of a signaling pathway important for dendrite arborization is regulated.
Although specific interactions between diverse cell surface molecules are proposed to regulate circuit formation, the extent to which these promote dendrite growth and branching is unclear. Here, using transgenic mice to manipulate expression in vivo, I and my colleagues show that the complexity of a cortical neuron’s dendritic arbor is regulated by γ-Pcdh isoform matching with surrounding cells. Expression of the same single γ-Pcdh isoform leads to exuberant or minimal arbor complexity depending on matched expression of surrounding cells. Additionally, loss of γ-Pcdhs in astrocytes, or induced mis-matching between astrocytes and neurons, reduces dendrite complexity in a cell non-autonomous manner. Thus, these data support our proposal that γ-Pcdhs create a rare neuronal identity that, depending on the identities of surrounding cells, specifies the complexity of that neuron’s dendritic arbor.
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Garrett, Andrew. "Control of synaptogenesis and dendritic arborization by the γ-Protocadherin family of adhesion molecules". Diss., University of Iowa, 2009. https://ir.uiowa.edu/etd/362.
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During development, the mammalian nervous system wires into a precise network of unrivaled complexity. The formation of this network is regulated by an assortment of molecular cues, both secreted molecules and cell-surface proteins. The ã-Protocadherins (ã-Pcdhs) are particularly good candidates for involvement in these processes. This family of adhesion molecules consists of 22 members, each with diverse extracellular adhesive domains and shared cytoplasmic domains. Thus, cellular interactions with varied adhesive partners can trigger common cytoplasmic responses. Here we investigated the functions of the ã-Pcdhs in two processes involved in neural network formation: dendrite arborization and synaptogenesis.
We first asked how ã-Pcdhs regulate synaptogenesis in the spinal cord. We found that the ã-Pcdhs are differentially expressed by astrocytes as well as neurons. In astrocytes, the proteins localize to perisynaptic processes where they can mediate contacts between neurons and astrocytes. In an in vitro co-culture system in which either only astrocytes or only neurons were null for the ã-Pcdhs, we found that astrocytic ã-Pcdh is required for an early stage of synaptogenesis in a contact-dependent manner, while neuronal ã-Pcdh is sufficient for later stages. Conversely, if neurons lacked the adhesion molecules, very few synaptic contacts formed at all. By deleting the ã-Pcdhs from astrocytes in vivo, we demonstrated that these contacts are required for the normal progression of synaptogenesis.
We also investigated the function of the ã-Pcdhs in the cerebral cortex. We found that cortical-restricted loss of the adhesion molecules resulted in a severe reduction in thickness of layer 1. By crossing the mutant mice to a line in which scattered layer 5 neurons express YFP, we saw that this thinning resulted from a reduced complexity in the apical tufts of dendrites from layer 5 neurons. Sholl analysis demonstrated that the arbor reduction existed throughout the cell, a phenotype that was recapitulated in vitro. Using the in vitro system, we found that the arborization defect was caused by hyperphosphorylation of the PKC substrate, MARCKS, indicating that the ã-Pcdhs may function by inhibiting PKC activity. Thus, we provide new information about the mechanisms through which the ã-Pcdhs influence neural network development.
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Ellender, Tommas Jan. "Perisomatic-targeting interneurons control the initiation of hippocampal population bursts". Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:9c9c34af-a20f-4c9c-9cb3-85f110a1e38e.
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Replay of spike sequences can be seen during sharp wave – ripple population burst activity in the hippocampus. It is thought that this activity, which occurs during rest and sleep, is involved in memory consolidation. The cellular mechanisms underlying the initiation of these replay events are not well understood. To investigate this, a hippocampal slice model, showing spontaneous sharp wave – ripple activity, and a combination of planar multi-electrode array recordings and whole-cell patch-clamp recordings of anatomically identified hippocampal neurons were used. Firstly, the spatial and temporal profile of sharp waves in vitro was analysed in detail. Sharp waves were generated by changing subpopulations of pyramidal neurons in the CA3 region and had characteristics similar to those found in vivo. Secondly, four major receptor types present in hippocampal CA3, namely NMDA, AMPA, GABAA and GABAB receptors, were investigated for their involvement in sharp wave generation. Surprisingly, not only AMPA receptor-mediated events, but also phasic GABAA receptor-mediated inhibition, were necessary for sharp wave generation. Thirdly, single perisomatic-targeting interneurons were activated. This experiment showed that induced spiking activity of an individual perisomatic-targeting interneuron can both suppress and subsequently enhance local sharp wave generation. Spiking activity of other neuron types (i.e. pyramidal neurons, dendritic-targeting interneurons and interneuron-selective interneurons) had no significant effect on sharp wave incidence. Finally, it is suggested that this post-inhibitory enhancement of sharp wave generation can be mediated by a transient increase in the ratio of excitation to inhibition in the local network. In conclusion, these results suggest a new role for perisomatic-targeting interneurons in controlling the local initiation of sharp waves by selectively suppressing and subsequently enhancing recruitment of a subpopulation of pyramidal neurons. These results further imply that interneurons may play an integral part in the local information processing that takes place in the hippocampal network.
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Singh, Deeba. "Phosphorylation sites on specific neuronal proteins can control the mode of synaptic vesicle exocytosis and thereby regulate synaptic transmission". Thesis, University of Central Lancashire, 2017. http://clok.uclan.ac.uk/23988/.
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Synaptic vesicles (SVs) can exocytose via Full fusion (FF) or by Kiss-and-Run (KR) mechanisms. In this thesis, synaptosomes prepared from adult rat cerebrocortex demonstrated that these modes can be switched by regulating the intracellular calcium levels and/or protein phosphorylation reactions. The stimuli employed were: 30 mM K+ (HK), 1 mM 4-aminopyridine (4AP) and 5 mM ionomycin (ION) together with 5 mM Ca2+. In this model employed, myosin-II and dynamins can regulate the closure of the fusion pore of the readily releasable pool (RRP) of SVs during KR but are independent of each other’s actions. In biochemical assays, synaptosomes were maximally labelled with FM2-10 dye such that both the RRP and the RP were loaded and such terminals were subsequently evoked to release the dye and this was compared to the endogenous release of glutamate (GLU). Results show that the rise in [Ca2+]i at the active zone produced by HK5C activates PKC isoforms, which in turn cause phosphorylation of myosin-II and dynamins. It is hypothesised that dynamins are active at relatively lower increases in [Ca2+]i that do not activate PKCs whereas myosin-II is active at relatively higher increases in [Ca2+]i that activate certain PKCs. Such activation of PKC stimulates myosin-II -but inhibits the action of dynamins – and it is this active protein that can close the fusion pore. ION5C, however, activates dynamin(s) but not myosin-II, and under such conditions dynamin can close the fusion pore. This dynamin-dependent KR mode is independent of clathrin because this is not perturbed by the blockade of clathrin action using the drug, pitstop2TM and the HK5C evoked myosin-II-dependent KR is independent of both clathrin and dynamin. Therefore, the KR mechanism described, herein, is distinct from ultra-fast endocytosis that has both a dynamin and clathrin dependence. Pre-treatment of synaptosomes with DYN and/or pitstop2TM prior to the initial pre-stimulation with HK5C inhibits all dynamin and clathrin dependent processes so that SVs that recycle after the HK5C pre-stimulation would be perturbed if they had such a requirement. Indeed, following this treatment some SVs were not released by ION5C, although, the 4AP5C evoked GLU release is not affected and it would appear that the 4AP5C sensitive pool (the RRP) can still release following blockade of dynamin and clathrin. This demonstrates that the RRP underwent KR during the first pre-stimulus (actually via a myosin-II- dependent process) and was available to release again during the second round, and again this cannot be via ultra-fast endocytosis. The role of cAMP and PKA pathways in regulating the modes was investigated. Adenylate cyclase activation by forksolin inhibits the release of the RP but switches all the RRP vesicles to KR when evoked by 4AP5C. Adenylate cyclase inhibition by 9-Cyclopentyl-Adenine (9-Cp-Ade) has no effect on GLU release or exocytotic mode. Forskolin’s action on the RP is due to a specific increase in cAMP, because pre-treatment of synaptosomes with 9-Cp-Ade before forskolin prevents the forkskolin action. The PKA activator, Sp-5,7-dichloro-cBIMPs (cBIMPS) does not affect evoked GLU release although it does switch some of the RP to a KR mode whereas inhibiting PKA with KT 5720 has not effect on GLU release but induces the RRP to undergo FF. Clearly, forskolin’s action on both the RP and the RRP SVs is distinct from PKA activation and it may work through activating the exchange protein directly activated by cAMP (EPAC). Previous experiments have showed that inhibition of protein phosphatase 2A (PP2A) by okadaic acid (OA) switches the RRP to FF for all stimuli, but OA pre-treatment before forskolin failed to prevent 4AP5C switching some SVs in the RRP from FF to KR. This suggests that an adenylate cyclase pathway can override the OA-sensitive pathway. The Seahorse extracellular flux analyser was used to measure various mitochondrial respiration parameters (basal, ATP production, spare capacity, maximum respiration, proton leakage and non-mitochondrial respiration). Employing 0.3 and 3 mM phenyl arsine oxide appears to perturb the spare respiratory capacity, whilst 0.1 mM did not. This indicated that we were previously using too high a concentration of this drug to study modes of exocytosis. Such a result led to the testing of the drugs employed in this study on exocytosis to check that they did no produce a non-specific effect on the bioenergetics of the synaptosomes: 9-Cp-Ade, Blebb, Go 6983, cBIMPs, forskolin or OA did not change the mitochondrial respiratory parameters indicating that any exocytotic effects shown were specific. The specific phosphorylation of Ser-778, Ser-774 and Ser-795 on dynamin 1 was investigated using well characterized commercial antibodies and western blotting. It was concluded that the phosphorylation of Ser-774 and Ser-778 showed no correlation with dynamin’s activity towards regulating closure of the fusion pore although these sites may well correlate with clathrin dependent endocytosis and bulk endocytosis. However, the phosphorylation of Ser-795 on dynamin may play an important role in the inhibition of dynamin’s activity towards closing the fusion pore during KR. Phosphorylation on Ser-795 may be under the regulation of PKC as demonstrated using a PKC activator, phorbol myristate acetate, and an inhibitor, Go 6983. Therefore, endogenous PKC activation may phosphorylate this site when a very high Δ[Ca2+]i is achieved at the active zone. It was difficult to obtain a conclusion as to which PKC isoform could regulate the mode of SV exocytosis by phosphorylation of Ser-795 on dynamin due to the low phosphorylation levels obtained whilst employing Go 6983 and Go 6976.
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Orłowski, Jakub. "Adaptive control of time-delay systems to counteract pathological brain oscillations". Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS605.
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Les oscillations beta (10-30 Hz) observées dans les ganglions de la base sont un bio-marqueur connu de la maladie de Parkinson. Leur intensité est corrélée à une augmentation des symptômes d'akinésie et de bradykinésie. La stimulation cérébrale profonde (SCP) conduit à une réduction de ces oscillations cérébrales ainsi qu'à une amélioration de la qualité vie du patient. La SCP actuellement utilisée en clinique est toutefois de nature boucle ouverte: les paramètres du signal de stimulation délivré sont constants, indépendamment de l'activité cérébrale ou de l'état du patient. Ceci peut conduire à une sur-stimulation, pouvant induire des effets secondaires et un raccourcissement de l'autonomie du stimulateur, ou au contraire à une sous-stimulation en cas de dégradation des symptômes. Des stratégies de SCP en boucle fermée, qui exploitent des mesures de l'activité cérébrale du patient pour adapter la stimulation en temps réel, constituent une approche prometteuse pour contrer ces limitations. Dans cette thèse, nous exploitons un modèle existant du taux de décharges neuronales de la boucle noyau sous-thalamique (STN) - globus pallidus externe (GPe) pour proposer une SCP proportionnelle adaptative.Nous analysons tout d'abord le modèle bouclé par une commande proportionnelle sur le STN et montrons qu'un gain proportionnel suffisamment élevé assure sa stabilité globale exponentielle (GES). A cette fin, nous proposons un nouveau critère, plus simple à appliquer que les conditions existantes, pour garantir la GES de systèmes globalement Lipschitz au moyen d'une fonctionnelle de Lyapunov-Krasovskii.Nous étendons ensuite l'approche par sigma modification, proposée initialement par Ioannou et Kokotovic, aux systèmes à retards et proposons des conditions explicites sous lesquelles cette commande adaptative stabilise le système. Nous montrons que cette loi de commande garantit alors une stabilité pratique, dans laquelle la norme L_1 de l'état sur une fenêtre temporelle suffisamment longue converge vers un voisinage de l'équilibre à une erreur près, dont l'amplitude peut être arbitrairement réduite par le réglage d'un paramètre de commande. Appliquée au modèle STN-GPe, cette stratégie conduit à une commande proportionnelle dont le gain s'ajuste automatiquement sur la base de mesures de l'activité du STN pour contrer les oscillations cérébrales pathologiques. L'analyse de la robustesse de cette stratégie vis-à-vis de perturbations ou de dynamiques non-modélisées nous a en outre conduit à réfuter, au travers d'un contre-exemple, un résultat existant sur la stabilité partielle des systèmes non-linéaires.Enfin nous illustrons, par des simulations sur une extension spatio-temporelle du modèle, que la stratégie de commande proposée est capable d'atténuer sélectivement les oscillations cérébrales, suivant leur gamme fréquentielle, qu'elles proviennent de la boucle STN-GPe elle-même ou d'entrées corticales du STNBeta oscillations (10-30 Hz) observed in the basal ganglia are a well-known biomarker of Parkinson's disease, correlated with increased symptoms of akinesia and bradykinesia. Deep brain stimulation (DBS) leads to a reduction of these oscillations, as well as improvement in the patients' quality of life. Clinically used DBS, however, is since its inception delivered in an open-loop fashion, where the parameters of the stimulation are constant regardless of the underlying brain activity and the state of the patient. This can lead to overstimulation, inducing side-effects and shortening battery life of the impulse generator, as well as understimulation when the symptoms of the disease worsen. Closed-loop DBS, exploiting measurements on the patient's brain activity to adapt the stimulation in real-time, is a promising way to overcome these limitations. In this thesis, we rely on an existing firing-rate model of the activity of the subthalamic nucleus (STN) - external globus pallidus (GPe) loop to propose an adaptive proportional DBS.We first analyze the model under proportional feedback and show that high-gain proportional stimulation makes the system globally exponentially stable (GES). To that aim, we propose a relaxed Lyapunov-Krasovskii condition for GES, valid for globally Lipschitz systems. We then extend the sigma modification approach, originally proposed by Ioannou and Kokotovic, to time-delay systems by providing explicit conditions under which this adaptive control stabilizes the system. We show that this controller then induces a practical stability property, in which the L_1 norm of the state over a sufficiently long time window converges to a neighborhood of the equilibrium up to a steady-state error that can be made arbitrarily small by tuning a control parameter. When applied to the STN-GPe firing-rate model, this leads to a proportional control law, whose gain is automatically adjusted based on the measured activity of the STN, to successfully disrupt pathological brain oscillations. In an attempt to assess the robustness of this adaptive control strategy to exogenous inputs or unmodeled dynamics, we also disprove an existing result on partial stability of nonlinear systems.Finally, we illustrate with numerical simulations on a spatiotemporal extension of this model that the proposed control law is capable of selectively quenching the pathological oscillations, based on their frequency band, regardles of whether the oscillations originate within the STN-GPe loop, or in the cortical neurons projecting to the STN
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Montpetit, Colin J. "Neuronal control of catecholamine release in the rainbow trout (Oncorhynchus mykiss)". Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/28961.
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The aim of this thesis was to study aspects of the neuronal control of catecholamine secretion in a teleost, the rainbow trout. The development and validation of a nerve stimulation technique made it possible to determine that a portion of the neuronal control of catecholamine release, which prevailed at low frequency stimulation, could be attributed to vasoactive intestinal polypeptide (VIP) and/or pituitary adenylate cyclase activating polypeptide (PACAP). On the other hand, cholinergic stimulation predominated during higher levels of neuronal activity. Fluorescent histochemical techniques in combination with pharmacological approaches provided direct evidence that VIP and PACAP can elicit the secretion of adrenaline, only, from the chromaffin tissue via specific VIP binding sites that exhibited properties of VPAC receptors.
Using in situ perfused posterior cardinal vein preparations, evidence was provided that while the nicotinic receptor appears to be the predominant pathway mediating the effects of acetylcholine on catecholamine secretion, muscarinic receptor stimulation may augment the cellular response to nicotinic receptor activation. Under extreme conditions, muscarinic receptors may directly elicit the secretion of catecholamines.
The impact of extracellular catecholamines on catecholamine secretion from chromaffin cells was also investigated. Results revealed that the mechanisms of adrenergic inhibition of catecholamine secretion in response to cholinergic stimulation include activation of chromaffin cell membrane beta2-receptors and presynaptic alpha2-adrenergic receptors. However, catecholamine release in response to VIP appears to be insensitive to the adrenergic negative feedback mechanisms.
Finally, despite the rapid progress in cDNA cloning, molecular information on the receptors mediating the effects of VIP and PACAP in fish is scant. In this thesis, I report preliminary findings of the cloning of the trout PAC1, VPAC1, and VPAC2 receptors from brain cDNA.
In summary, VIP and PACAP appear to function as neurotransmitters in the neuronal regulation of catecholamine release in this species. The apparent complexity of the mechanisms regulating the secretion of catecholamines from trout chromaffin cells may reflect the precise control required for these hormones to play their role in physiological and biochemical homeostasis in these organisms.
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Yen, Jasper Tong-Biau. "Force control during human bouncing gaits". Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/43698.
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Every movement has a goal. For reaching, the goal is to move the hand to a specific location. For locomotion, however, goals for each step cycle are unclear and veiled by the automatic nature of lower limb control. What mechanical variables does the nervous system "care" about during locomotion? Abundant evidence from the biomechanics literature suggests that the force generated on the ground, or endpoint force, is an important task variable during hopping and running. Hopping and running are called bouncing gaits for the reason that the endpoint force trajectory is like that of bouncing on a pogo stick. In this work, I captured kinematics and kinetics of human bouncing gaits, and tested whether structure in the inherent step-to-step variability is consistent with control of endpoint force. I found that joint torques covary from step to step to stabilize only peak force. When two limbs are used to generate force on the ground at the same time, individual forces of the limbs are not stabilized, but the total peak force is stabilized. Moreover, passive dynamics may be exploited during forward progression. These results suggest that the number of kinetic goals is minimal, and this simple control scheme involves goals for discrete times during the gait cycle. Uncovering biomechanical goals of locomotion provides a functional context for understanding how complex joints, muscles, and neural circuits are coordinated.
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Kang, Jing. "Discrimination and control in stochastic neuron models". Thesis, University of Warwick, 2009. http://wrap.warwick.ac.uk/3155/.
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Major topics of great interest in neuroscience involve understanding the brain function in stimuli coding, perceptive discrimination, and movement control through neuronal activities. Many researchers are designing biophysical and psychological experiments to study the activities of neurons in the presence of various stimuli. People have also been trying to link the neural responses to human perceptual and behavioral level. In addition, mathematical models and neural networks have been developed to investigate how neurons respond and communicate with each other. In this thesis, my aim is to understand how the central nervous system performs discrimination tasks and achieves precise control of movement, using noisy neural signals. I have studied, both through experimental and modelling approaches, how neurons respond to external stimuli. I worked in three aspects in details. The first is the neuronal coding mechanism of input stimuli with different temporal frequencies. Intracellular recordings of single neurons were performed with patch-clamp techniques to study the neural activities in rats somatosensory cortices in vitro, and the simplest possible neural model—integrate-and-fire model—was used to simulate the observations. The results obtained from the simulation were very consistent with that in the experiments. Another focus of this work is the link between the psychophysical response and its simultaneous neural discharges. I derived that under a widely accepted psychophysical law (Weber’s law), the neural activities were less variable than a Poisson process (which is often used to describe the neuron spiking process). My work shows how psychophysical behaviour reflects intrinsic neural activities quantitatively. Finally, the focus is on the control of movements by neural signals. A generalized approach to solve optimal movement control problems is proposed in my work, where pulses are used as neural signals to achieve a precise control. The simulation results clearly illustrate the advantage of this generalized control. In this thesis, I have raised novel, insightful yet simple approaches to study and explain the underlying mechanism behind the complexity of neural system, from three examples on sensory discrimination and neural movement control.
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Tomasevic, Leo. "Non invasive investigation of sensorimotor control for future development of brain-machine-interface (BMI)". Thesis, University of Plymouth, 2014. http://hdl.handle.net/10026.1/3161.
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My thesis focuses on describing novel functional connectivity properties of the sensorimotor system that are of potential interest in the field of brain-machine interface. In particular, I have investigated how the connectivity changes as a consequence of either pathologic conditions or spontaneous fluctuations of the brain's internal state. An ad-hoc electronic device has been developed to implement the appropriate experimental settings. First, the functional communication among sensorimotor primary nodes was investigated in multiple sclerosis patients afflicted by persistent fatigue. I selected this condition, for which there is no effective pharmacological treatment, since existing literature links this type of fatigue to the motor control system. In this study, electroencephalographic (EEG) and electromyographic (EMG) traces were acquired together with the pressure exerted on a bulb during an isometric hand grip. The results showed a higher frequency connection between central and peripheral nervous systems (CMC) and an overcorrection of the exerted movement in fatigued multiple sclerosis patients. In fact, even though any fatigue-dependent brain and muscular oscillatory activity alterations were absent, their connectivity worked at higher frequencies as fatigue increased, explaining 67% of the fatigue scale (MFIS) variance (p=.002). In other terms, the functional communication within the central-peripheral nervous systems, namely involving primary sensorimotor areas, was sensitive to tiny alterations in neural connectivity leading to fatigue, well before the appearance of impairments in single nodes of the network. The second study was about connectivity intended as propagation of information and studied in dependence on spontaneous fluctuations of the sensorimotor system triggered by an external stimulus. Knowledge of the propagation mechanisms and of their changes is essential to extract significant information from single trials. The EEG traces were acquired during transcranial magnetic stimulation (TMS) to yield to a deeper knowledge about the response to an external stimulation while the cortico-spinal system passes through different states. The results showed that spontaneous increases of the excitation of the node originating the transmission within the hand control network gave rise to dynamic recruitment patterns with opposite behaviors, weaker in homotopic and parietal circuits, stronger in frontal ones. As probed by TMS, this behavior indicates that the effective connectivity within bilateral circuits orchestrating hand control are dynamically modulated in time even in resting state. The third investigation assessed the plastic changes in the sensorimotor system after stroke induced by 3 months of robotic rehabilitation in chronic phase. A functional source extraction procedure was applied on the acquired EEG data, enabling the investigation of the functional connectivity between homologous areas in the resting state. The most significant result was that the clinical ameliorations were associated to a ‘normalization’ of the functional connectivity between homologous areas. In fact, the brain connectivity did not necessarily increase or decrease, but it settled within a ‘physiological’ range of connectivity. These studies strengthen our knowledge about the behavioral role of the functional connectivity among neuronal networks’ nodes, which will be essential in future developments of enhanced rehabilitative interventions, including brain-machine interfaces. The presented research also moves the definition of new indices of clinical state evaluation relevant for compensating interventions, a step forward.
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Fuller, David Dwight 1970. "Respiratory-related control and functional significance of tongue protrudor and retractor muscles". Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/282801.
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The mammalian upper airway includes the larynx, pharynx, and nose. Respiratory-related contraction of the skeletal muscles situated in and around these regions influences upper airway diameter and compliance. The pharynx is the most collapsible upper airway segment, and its diameter and compliance depend in part on tongue position and stiffness. These parameters are controlled by the genioglossus (GG) muscle, which protrudes the tongue, and the hyoglossus (HG) and styloglossus (SG) muscles, which retract the tongue. Prior work has focused almost exclusively on the GG, leaving a gap in the literature regarding the respiratory control and function of the tongue retractors. Accordingly, our overall purpose was to test the hypothesis that the tongue protrudor and retractor muscles are co-activated during inspiration and that co-activation promotes airway patency. Experiments were conducted using supine, anesthetized, tracheotomized rats. Tongue movements were quantified as either protrusive or retractive by connecting the tip of the tongue to a force transducer. The protrudor and retractor muscles were co-activated during quiet breathing and their activities increased in parallel when breathing was stimulated with high CO2 or low O 2. Co-activation of protrudor and retractor muscles was always accompanied by tongue retraction. Neural drive to both GG and HG muscles was increased in parallel when lung volume feedback was removed by single breath tracheal occlusion. The functional significance of tongue muscle co-activation was examined using an isolated upper airway preparation. Co-activation increased airflow rates and stiffened the airway, whereas selective protrudor muscle activation increased airflow but did not alter airway stiffness. A standard fatigue protocol was used to examine the influence of hypoxia on the endurance performance of tongue protrudor and retractor muscles; the results indicate that hypoxia attenuates tongue muscle endurance, possibly via impaired neuromuscular transmission. It is concluded that, in the rat, (1) the tongue protrudor and retractor muscles are co-activated during inspiration, and respond in parallel to increases in respiratory drive; (2) tongue muscle co-activation results in tongue retraction and stiffening of the pharyngeal airway, and (3) the endurance of the tongue muscles is impaired during hypoxia.
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Gordon, Kara Leigh. "TorsinA and protein quality control". Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2708.
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DYT1 dystonia (DYT1) is a disabling inherited neurological disorder with juvenile onset. The genetic mutation in DYT1 leads to the deletion of a glutamic acid (E) residue in the protein torsinA. The function of torsinA and how the mutation leads to DYT1 is poorly understood. We hypothesize that how efficiently the disease-linked mutant protein is cleared may be critical for DYT1 pathogenesis. Therefore we explored mechanisms of torsinA catabolism, employing biochemical, cellular, and animal-based approaches. We asked if torsinA(wt) and torsinA(DE) are degraded preferentially through different catabolic mechanisms, specifically the ubiquitin proteasome pathway (UPP) and autophagy. We determined that torsinA(wt) is cleared by autophagy while torsinA(DE) is efficiently degraded by the UPP suggesting degradation processes can modulate torsinA(DE) levels. Proteins implicated in recognizing motifs on torsinA(DE) for targeting to the UPP represent candidate proteins that may modify DYT1 pathogenesis. We examined how removal of the hydrophobic domain and mutation of glycosylated asparagine residues on torsinA altered stability and catabolic mechanism. We found the glycosylation sites on torsinA are important for stability modulate its degradation through the UPP. F-box G-domain protein 1 (FBG1) has been implicated in degradation of glycosylated ER proteins. We hypothesized that FBG1 would promote torsinA degradation and demonstrated that FBG1 modulates levels of torsinA in a non-canonical manner through the UPP and autophagy. We examined if lack of FBG1 in a torsinA(DE) mouse model altered motor phenotypes. We saw no effect which suggests FBG1 does not alter DYT1 pathogenesis despite its promotion of torsinA(DE) degradation. In addition, we explored a potential mechanism for the previously described role of torsinA in modulating cytoplasmic protein aggregation. We hypothesized this endoplasmic reticulum (ER) resident protein would indirectly alter cytoplasmic protein aggregation through modulation of ER stress. We employed a poly-glutamine expanded repeat protein and pharmacological ER stressors to determine that torsinA does not alter poly-glutamine protein aggregation nor ER stress in a mammalian system. In summary, this thesis suggests proteins involved in the catabolism of torsinA(DE) may modify DYT1 pathogenesis and that torsinA and its DYT1-linked mutant are model proteins for investigating ER protein degradation by the UPP and autophagy.
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Platt, Nicola J. "Investigating the presynaptic control of striatal dopamine release". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:5af7e14b-4411-43ad-9902-44cbd6d170cb.
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Dopamine (DA) is a key neuromodulator in the striatum, and is important for action selection and reinforcement learning. Dysfunctions in striatal DA signalling contribute to numerous disorders including Parkinson’s disease (PD) and drug addiction. Midbrain DA neurons switch from low to high frequency firing in response to reward-related events, which is proposed to increase striatal DA release. However, in addition to DA neuron firing pattern, striatal DA signalling depends upon the short-term plasticity of DA release, which is controlled by presynaptic and local network factors. This thesis uses fast-scan cyclic voltammetry, in murine striatal slices, to detect subsecond changes in extracellular DA, and investigate the presynaptic control of striatal DA release and release plasticity. Acetylcholine from striatal cholinergic interneurons, acting at nicotinic receptors (nAChRs) on DA terminals, is one factor that strongly influences DA release. This thesis particularly explores how presynaptic factors interact with nAChRs to control DA release. Firstly, release probability, a key determinant of release plasticity at many synapses, was found to be only weakly related to DA release plasticity, and only when nAChRs are inactive. Secondly, a direct role of the DA uptake transporter (DAT) in controlling DA release plasticity was identified, when nAChRs are inactive. Thirdly, regional differences were identified in the role of the DAT in controlling DA release via control of D2 receptor activation, when nAChRs are active. Finally, mutant α-synuclein, which causes PD in humans, was found to only subtly affect striatal DA release. These data suggest that the control of striatal DA release differs substantially from other central transmitters. Release probability and α-synuclein play only minor roles, but nAChRs and the DAT significantly control DA release plasticity. These findings review our understanding of striatal DA release and may have implications for understanding the actions of drugs of abuse and early PD pathogenesis.
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Drummond, Neil M. "Inhibitory Control Processes During the Preparation and Initiation of Motor Responses". Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35690.
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The ability to stop ongoing movements or prevent unwanted movements is fundamental to behavioural control. This thesis addresses the neural processes underlying inhibitory control and how initiation and stop processes interact to control behaviour. We conducted four studies, employing various behavioural tasks that require humans to prepare to initiate a response with the possibility that it may have to be prevented or stopped from being initiated. In the first experiment we sought to determine whether the increase in reaction time (RT) during the performance of traditional stop-signal task was due to a decreased the amount of go-related preparatory activation. We used a startling acoustic stimulus (SAS) to determine whether the go-response could be triggered involuntarily, and investigated whether the latency of SAS responses were delayed when participants were instructed that they might have to stop their response compared to when they knew they would never stop (i.e., simple RT task). We found that the go-response was prepared in advance during the stop-signal task, but to a lesser degree as indicated by the slower SAS response latency, compared to when go trials were completed in the simple RT task. Thus, even the possibility of having to stop a response reduces the level of preparatory go-activation.
The second experiment tested the hypothesis that behavioural control during a stop-signal task is determined by an independent race between go- and stop-processes. In this experiment we used a SAS to manipulate initiation and inhibition by probing the go- and stop-response prior to and after the stop-signal respectively in a stop-signal task. We found that the go-response could be triggered by the SAS even 200 ms following the stop-signal suggesting that behavioural control during a stop-signal task is not determined by an independent race between go- and stop-activations, but rather by an interaction between go-activation and stop processes.
The third experiment investigated the effect of advance preparation on the ability to proactively and selectively inhibit a single limb in a bimanual response that had been cued to maybe stop. TMS was used to measure the excitability of the limb that was cued to maybe stop in comparison to the limb that was to continue with its response. In addition, a SAS was used to probe the preparatory state of the go-response in each limb. We found that increased preparatory go-activation of responses in both limbs overshadowed the neurophysiological evidence of proactive selective inhibition, while processes related to the selective stopping task appeared to suppress subcortical motor structures and the ability of the SAS to involuntarily trigger the prepared responses.
The fourth experiment sought to determine the role of the right inferior frontal gyrus (rIFG) and the pre-supplementary motor area (preSMA) in the inhibition of response initiation during a go/no-go task. We temporarily deactivated rIFG or preSMA using continuous theta burst stimulation (cTBS) and examined changes in inhibition, voluntary initiation, and the ability of a SAS to involuntary trigger the initiation of the response. We found that stimulation to both cortical sites impaired participant’s ability to withhold movements during no-go trials. Notably, deactivating rIFG and preSMA did not affect voluntary initiation and did not enable the SAS to involuntarily trigger the response. These findings implicate the rIFG and the preSMA in the ability to inhibit responses during a go/no-go task, and suggests that preparation and initiation of the go-response occurs in response to the imperative stimulus, with inhibition only applied once the stimulus is identified as a no-go signal.
Taken together, these studies show that i) modulation of preparatory go-activation contributes to the ability to inhibit a motor response, ii) motor response inhibition is achieved by initiation activation being prevented from reaching threshold, iii) preparatory go-activation overshadows proactive inhibition, iv) inhibitory control depends on the integrity and recruitment of top-down inhibitory control to suppress initiation activation once a no-go stimulus is identified. This research speaks to the interaction between initiation and inhibition processes and provides novel insight and evidence in support of an interactive model of inhibitory control.
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Cohen, Zvi 1967. "Central serotonin (5-HT) neurons in the control of the cerebral circulation : anatomical basis and functional receptors". Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37543.
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Serotonin (5-hydroxytryptamine, 5-HT) is known to influence cerebrovascular functions such as local cerebral blood flow (CBF) and blood brain barrier (BBB) permeability, and has been implicated in cerebrovascular diseases. The present study used a multifaceted approach to determine the distribution, density and origin of the 5-HT innervation of blood vessels at the base of the brain and overlying the cerebral cortex as well as those embedded in the cortical parenchyma. In addition, the type(s) of 5-HT receptor(s) present on intracortical blood vessels as well as their precise cellular localization within the vessel wall was investigated.Firstly, in extracerebral blood vessels, we showed that perivascular serotonergic nerve fibers, immunocytochemically identified for the 5-HT synthesizing enzyme, tryptophan hydroxylase (TPH), are greatly reduced following removal of the superior cervical ganglia, but not after specific lesion of the ascending 5-HT fibers originating from the brainstem raphe nuclei. In addition, we demonstrated that the distribution pattern of TPH-immunolabelled perivascular fibers differed from those containing noradrenaline (identified by dopamine-beta-hydroxylase). These results suggest the existence of a subset of distinct 5-HT nerve fibers in extracerebral arteries and that the serotonergic innervation; most probably, arises from the superior cervical ganglia or a structure closely related to it.
Secondly, in investigating the serotonergic input to the intraparenchymal microcirculation at the ultrastructural level, we found that central TPH-containing nerve terminals are intimately associated with intraparenchymal blood vessels and that these neurovascular associations were closer and/or more frequent in brain regions where manipulations of the brainstem raphe neurons elicited significant changes, as compared to relatively unresponsive cerebral area. These associations frequently involved the perivascular astrocytes, suggesting a possible intermediary role for these non-neuronal cells in the control of microvascular functions. Furthermore, the associations between 5-HT-synthesizing nerve terminals with the microvascular bed appeared relatively selective since neurovascular noradrenaline nerve terminals in the same cortical subdivision did not share the same characteristics in terms of frequency, intimacy or distribution around the vessel walls.
Finally, in an attempt to identify the exact site(s) of action of 5-HT on the blood vessels, we characterized, via reverse transcriptase-polymerase chain reaction and second messenger assays, the 5-HT receptor(s) present on human intracortical blood vessels as well as in cell cultures of human brain astrocytes and of endothelial and smooth muscle cells of micro-vascular origin. We reported the differential expression not only of messages but also of functional proteins for specific 5-HT receptor subtypes in the different cellular compartments of the blood vessel wall; a finding fully compatible with the ability of 5-HT to regulate microvascular perfusion and BBB permeability.
Altogether, the present thesis provides an anatomical substrate for the 5-HT-mediated responses in the microvascular bed. It demonstrates that the indoleamine can affect the microvascular bed by interacting either directly with endothelial and/or smooth muscle cells or indirectly with the perivascular astroglial cells suggesting that the neuronal-glial-vascular triad most likely constitutes the functional unit in the regulation of microvascular related responses. These studies are likely to contribute significantly to our understanding of the relationships between 5-HT and non-neuronal vascular and astroglial cells as they relate to the mechanisms involved in the regulation of CBF and BBB.
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Chua, Winnie Wei Ling. "Interactions between force and timing control of repeated actions". Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6286/.
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Variability is an inherent component in movement and provides an insight into control processes involved in producing motor responses. This thesis investigates the interactions between force and timing processes in the production of repetitive actions from an information processing perspective. Force-time interactions are examined in steady state sequences, sequences with step changes, and steady state sequences with a secondary visual search task as an attentional load. The account of control in normal healthy participants is then applied to describe behaviour of patients with cerebrovascular accidents (CVAs) in two case studies. Interaction was found to be present in variability measures and was quantified using cross-correlation analysis. Overall, results demonstrated that one locus of force-time interaction is at a cognitive level where motor responses are organised for execution. Corresponding changes in magnitude of dependence according to availability of attentional resources and task prioritisation supported this observation. Dependence patterns in patients with CVAs reflected loss of control when task difficulty increased. Finally, based on the findings, a conceptual model describing the interaction is proposed towards the development of a formal model for simulation studies.
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Vanes, Lucy Denise. "A systems neuroscience perspective on treatment resistant schizophrenia : the role of cognitive control, reinforcement learning, and myelination". Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/a-systems-neuroscience-perspective-on-treatment-resistant-schizophrenia(b453e9a9-03f2-42fd-a676-614b032f7de7).html.
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Approximately a third of patients with schizophrenia do not respond to antipsychotic treatment targeting the dopamine system, suggesting that a separable neural dysfunction may drive psychosis in these patients. This thesis aims to probe the mechanisms underlying treatment response by investigating two cognitive processes which have been implicated in schizophrenia – cognitive control and reinforcement learning – as well as brain myelination. The key hypotheses are that 1) treatment resistant schizophrenia emerges due to a failure to exert cognitive control, characterised by prefrontal hypoactivation and functional dysconnectivity, 2) treatment responsive schizophrenia is selectively associated with a subcortical dopaminergic dysfunction, evident in an abnormal neural signature of reward prediction error (RPE) during reinforcement learning, and 3) treatment resistant schizophrenia is characterised by exacerbated structural dysconnectivity as indexed by myelin content. To dissect these mechanisms, performance and neural activation during a cognitive control task and a reinforcement learning task, as well as myelin water fraction (MWF) were compared between 22 treatment resistant patients, 21 treatment responsive patients, and 24 healthy controls. Treatment resistant and responsive patients showed similarly impaired performance on both tasks compared to controls. During the cognitive control task, resistant patients showed an inverse correlation between frontal activation and psychotic symptoms as well as reduced functional fronto-thalamic connectivity compared to controls. During the reinforcement learning task, responsive patients showed reduced cortical and subcortical RPE related activation compared to controls and treatment resistant patients. MWF was reduced in patients compared to controls in several white matter regions but did not differ between the two patient groups. The findings support distinct neural mechanisms underlying treatment resistant and responsive schizophrenia despite similar behaviour. Functional dysconnectivity within the cognitive control network and a deterioration of frontal activation as a function of symptom severity may perpetuate psychosis despite dopaminergic treatment in treatment resistant schizophrenia, although this is not reflected in an exacerbated myelin dysfunction. The results highlight the importance of stratifying patient samples by treatment response status in future research.
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Yusainy, Cleoputri. "Overcoming aggression : musing on mindfulness and self-control". Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/13467/.
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The ability to restrain oneself from acting on aggressive impulses is arguably a crucial aspect of human functioning and interaction. Yet growing evidence in the literature suggests that people’s self-control resources may be limited and, at times, self-controlled regulation could even increase the association between aggressive triggers and aggressive behaviour. As an alternative, mindfulness practices encourage individuals to be aware and accept their aggression-related thoughts and emotions simply as an ephemeral state rather than to control them. Across four studies, we investigated the possibility that brief, as opposed to extensive, mindfulness exercise may reduce aggression, and whether this potential effect can be separated from a general mechanism of self-control. The relationships between mindfulness, self-control, and aggression were explored in their dispositional forms (Study 1; N = 241). Then, the effect of brief laboratory inductions of mindfulness was tested following manipulations designed to either bolster (Study 2; N = 99) or weaken (cross-cultural samples: Study 3; N = 119 vs. Study 4; N = 110) the resources of self-control. In addition, the potential roles of individual differences in sensitivity to provocations (SP) and frustrations (SF), and self-harm on aggression were also assessed. Results indicated that (i) despite one’s dispositional ability to exert self-control, the presence of a mindful quality uniquely reduced the experiences of anger and hostility, (ii) under the condition of full self-control resource (i.e., after self-control training), mindfulness induction contributed only in reducing more subtle/implicit forms of aggression, and (iii) under lack of self-control resource (i.e., following ego-depleting task), mindfulness induction significantly reduced direct physical aggression after the experience of provocation across cultures. The benefit of mindfulness on aggression appears to be more salient when individual’s self-control resource has been taxed, which operates similarly in Western and non-Western settings. Therapeutic tools focusing on the mechanism for controlling the expression of aggression would benefit from an inclusion of mindfulness-based strategies, as well as an early identification of individual’s sensitivity to different types of aggressive triggers and risks for self-harm.
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Chéry, Nadège. "Inhibitory control of neurons in the marginal zone (lamina I) of the rat spinal cord". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0032/NQ64534.pdf.
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McFarlane, Sarah. "Developmental control of voltage-gated potassium currents on postnatal rat peripheral neurons". Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=39454.
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Voltage-gated potassium (K) channels are important in controlling a neuron's excitability. In this thesis I show that neonatal rat nodose and superior cervical ganglion (SCG) neurons express three voltage-gated K currents: a non-inactivating delayed rectifier type current (IK); a rapidly inactivating A-current (IAf), and; a slowly inactivating A-current (IAs). The channels that underlie IAf and IAs differ in their voltage-dependent, kinetic and pharmacological properties, but share the same single channel conductance, suggesting that rapidly and slowly inactivating A-channels are distinct subtypes of the same basic channel. My preliminary molecular biology experiments establish an approach for identifying the genes that encode for IAf, IAs and IK channels on SCG neurons. By studying the expression of IAf, IAs and IK on peripheral neurons during the first 2 postnatal weeks, I showed that there is no change in the expression of the 3 currents on nodose neurons, whereas the outward current on SCG neurons changes significantly from one dominated by IAs to one dominated by IAf. These results indicate that the pattern of developmental expression of similar types of K channels can differ for each neuron type. Next, I investigated various factors involved in the postnatal control of expression of K channels on SCG neurons. I demonstrated that neither preganglionic nor target factors influence postnatal changes in K currents. However, I observed that neonatal SCG neurons that develop in culture without other cell types lose their expression of IAf and IAs, suggesting that extrinsic factor(s) are involved in the regulation of the expression of these currents. I showed that this loss of A-currents is due, in part, to the absence of a soluble factor provided by nonneuronal cells. In addition, my analysis of the different patterns of expression of voltage-gated K currents suggests that peripheral neurons use intrinsic mechanisms to coordinate their expression of IAf, IAs and
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White, James David. "A controlled comparative investigation of large group therapy for generalised anxiety disorder - "stress control"". Thesis, University of Glasgow, 1989. http://theses.gla.ac.uk/3708/.
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One hundred and nine generalised anxiety disorder (GAD) patients, referred by their General Practitioners to a clinical psychology primary care service, were assigned to either Cognitive, Behavioural, Cognitive-behavioural, Placebo or Waiting List conditions. `Stress Control' large group therapy combined didactic therapy with a workshop model and emphasised the aim of turning patients into their own `therapists' in order to enable them to deal with present and future problems. Patients were thus encouraged to view Stress Control as an `evening class' rather than `group therapy'. Measures of treatment process and outcome were obtained mainly from self-report instruments. Follow-up data were collected at six months post-treatment. At post-therapy, all active therapy conditions and, against expectation, the Placebo condition had shown significant time within treatment group change. The active therapy conditions, and to a lesser extent, the Placebo condition, were significantly different to the Waiting List condition, which, overall showed no evidence of improvement. At follow-up the active therapy condition generally enhanced therapy gains while the placebo condition maintained therapy gains. Process measures did not, with the exception of self-statement change, differentiate between the groups. Noted variable response in the main analyses was somewhat explained by various sub-group analyses. There appeared to be little benefit in dividing patients into those who experienced panic and those who did not. There was some evidence that `matching' patients to therapy, i.e. cognitive responders to cognitive therapy was of value at post-therapy although differences generally disappeared at follow-up. Synchronous change was associated with enhanced performance. Finally, attempts to predict response to Stress Control by a comparison of responders and non-responders were attempted and the results assessed in terms of clinical as opposed to statistical significance. The results of the present study are discussed with reference to other treatment outcome studies and an attempt to produce a model to account for the similar effects found across treatment conditions. The implications of these findings and some suggestions for future research for GAD and other diagnostic categories are discussed.
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Watson, Amanda Joyce. "Individual Differences in Inhibitory Control Skills at Three Years of Age". Thesis, Virginia Tech, 2011. http://hdl.handle.net/10919/42162.
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Seventy-three children participated in an investigation of inhibitory control (IC) at 3 years of age. Child IC was measured under various conditions in order to determine the impact that nonverbal and/or motivational task demands had on child IC task performance. Furthermore, task performance was examined with respect to measures of language, temperament, and psychophysiology. Tasks showed different patterns of relations to each of these variables. Furthermore, performance on the Hand Game, our measure of nonverbal IC, was explained by frontal EEG activity and, surprisingly, by language abilities. In contrast, performance on two other IC tasks, Day-Night and Less is More, was not related to measures of language or frontal EEG, perhaps because children performed at chance level on these tasks, indicating that these tasks may be too difficult for 3-year-old children. Implications of these findings are discussed.Master of Science