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The development of the human cortex: a neuroanatomical and histochemical study. / CUHK electronic theses & dissertations collectionJanuary 2001 (has links)
by Sau Cheung Tiu. / Thesis (M.D.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (p. 348-388). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.
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Functional study of LIM-homeodomain proteins Lhx1 and Lhx5 in the maintenance of cerebellar Purkinje neurons in the postnatal and adult mouse. / CUHK electronic theses & dissertations collectionJanuary 2012 (has links)
蒲金氏細胞(Purkinje cell)是小腦中的一種主要神經元,其主要作用在於協調身體活動及平衡。蒲金氏細胞之早期分化需要兩個密切相關的LIM同源盒結構域基因Lhx1及Lhx5。在胚胎小腦發育期間,這兩個基因的失活化會導致蒲金氏細胞數量大量減少。但有趣的是,就算在蒲金氏細胞完成分化之後,Lhx1/5之表達依然維持在高水平。這顯示Lhx1/5在產後小腦發育過程中可能有更多作用。為了研究這些可能作用,我把條件性Lhx1/5雙基因剔除小鼠和Pcp2-IRES-Cre轉基因小鼠交配,從而令Lhx1/5在產後第二天的蒲金氏細胞失活化。結果顯示Lhx1/5雙突變體老鼠在出生後兩星期即有顯著但程度不太大的運動失調。但在八星期,牠們出現嚴重的運動協調及身體平衡能力缺失。可是,擁有一個正常的Lhx1或Lhx5等位基因的控制小鼠並沒有這些不正常行為出現。在出生後的三個星期內,缺乏Lhx1/5會導致蒲金氏細胞樹突不正常發展,但小腦的整體細胞結構和分層卻維持正常。另外,這兩個基因對維持蒲金氏細胞已發展的樹突並不起作用,而且在六個月大的成年突變小鼠並沒有蒲金氏細胞退化。利用微陣列及逆轉錄聚合酶鏈式反應,我們在成年突變小鼠的小腦中確定了數個參與在麩胺酸及鈣訊息的突觸基因表達量下降。而這些突觸基因也在其他運動失調小鼠有下降的表達量。研究結果說明了Lhx1及Lhx5對蒲金氏細胞樹突發展有著重要、但功能重疊的作用。 / 在探究Lhx1/5如何控制蒲金氏細胞樹突發展時,我們發現Lhx1/5與Foxp4有蛋白質交互作用。Foxp4屬forkhead家族成員轉錄因子,它表達在小腦原基、遷移中及成熟的蒲金氏細胞。為了初步瞭解Foxp4在蒲金氏細胞發展中的作用,我在產後第十天小腦薄片組織培養中,利用siRNA降低Foxp4基因的表達量。結果發現蒲金氏細胞樹突及關聯的伯格曼膠質細胞支架出現結構性受損。這顯示Foxp4對維持蒲金氏細胞樹突有重要作用。 / 為了進一步研究Foxp4在活體蒲金氏細胞及小腦發育的作用,我把條件性Foxp4基因剔除小鼠和不同的Cre轉基因小鼠交配,從而令Foxp4在不同的發育過程階段中失活化。但是有趣地,我只能在同質結合突變小鼠 (Foxp4Δ/Δ),即Foxp4在生殖細胞時期已經被剔除的情況下,觀察到小腦發育遲緩。當Foxp4在其他發育過程階段中失活化,我並沒有觀察到任何缺陷表型。這個結果顯示了在活體中發生了功能性的彌補,但在小腦薄片組織培養中卻沒有發生。另外,條件性Lhx1/5雙基因剔除小鼠和條件性Foxp4基因剔除小鼠的不同表型意味著在控制蒲金氏細胞及小腦發育過程中,有其他蛋白質可能參與在Lhx1/5及Foxp4的轉錄複合子中。我們需要更多的研究去明白Foxp和 LIM同源盒結構域蛋白質在功能上的聯系及它們在中樞神經系統發育中的作用。 / Purkinje cells (PCs) are one of the principal neurons in the cerebellum that is essential for the coordination of fine-tuning body movement and balancing. Early differentiation of PCs requires two closely related LIM-homeodomain genes Lhx1 and Lhx5, as inactivation of both genes results in significant reduction of PC number in embryonic cerebellum. Interestingly, high levels of Lhx1/5 expressions persist even after PC differentiation in the postnatal cerebellum. Hence, there may be additional roles for these two genes during postnatal PC development. To address this question, conditional inactivation approach was used to inactivate both Lhx1/5 in postnatal PCs specifically beginning at postnatal day 2 (P2). Lhx1/5 double conditional knockout (DKO) mutants were generated by crossing Lhx1/5 conditional null mutant mice with Pcp2-IRES-Cre mice. The mutants initially showed modest but noticeable ataxic locomotion at around two weeks after birth. However at 8 weeks old, the mutants displayed severe deficits in motor coordination and body balance. The control animals with one functional copy of either Lhx1 or Lhx5 did not show any abnormality. Deficiencies of both genes could lead to abnormal PC dendritogenesis during the first three weeks of life although the general cytoarchitectural lamination of cerebellar cortex was maintained. However, the two genes were dispensable for the maintenance of developed dendrites in adult mouse and no PC degeneration was observed in the 6 month-old double mutant mouse. Further microarray and semi-quantitative RT-PCR analysis identified down-regulation of several synaptic genes that involved in glutamate and/or calcium signaling in our Lhx1/5 DKO mutant and such disturbance had also been found in other ataxic mouse models. Overall, our findings suggest that Lhx1/5 are required but functionally redundant in dendritogenesis of PCs. / During investigation on how Lhx1/5 control the dendritogenesis of PCs, Lhx1/5 proteins were found to physically interact with Foxp4. Foxp4 belongs to the forkhead transcription factor family that is expressed in developing cerebellum primordium, migrating and mature PCs. To initially examine the function of Foxp4 in PC development, Foxp4 was knocked down by siRNA in organotypic cerebellar slice culture at P10. Impaired organization of PC dendritic arbors and associated Bergmann glial scaffold were resulted, suggesting that Foxp4 is essential for the maintenance of PC dendritic arborization. / To further investigate the function of Foxp4 during the cerebellum and PCs development in vivo, a Foxp4 CKO mouse line was generated and crossed with different lines of Cre-deleter mice, including Zp3-Cre, Pax2-Cre, En1-Cre and Pcp2-IRES-Cre, to inactivate Foxp4 at different developmental stages. Intriguingly, although developmental delay of cerebellum was found in germline deletion of Foxp4 homozygous recombined null mutant, no defective phenotype was observed when Foxp4 was inactivated at other stages. Hence, functional compensation might take place in vivo but not in the cerebellar slice culture. The phenotypic difference between Lhx1/5 DKO and Foxp4 CKO mice imply potential involvement of other proteins in the transcription complex between Lhx1/5 and Foxp4 in regulating the cerebellum and/or PCs development. Thus further investigation is required to understand the functional association between Foxp and LIM-homeodomain protein families during the development of central nervous system. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Tam, Wing Yip. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 187-203). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.1 / 摘要 --- p.4 / Acknowledgements --- p.6 / Abbreviations --- p.8 / Figure list --- p.12 / Table list --- p.15 / Chapter Chapter 1 --- General Introduction --- p.16 / Chapter 1.1 --- An overview of cerebellum functions and anatomy --- p.16 / Chapter 1.2 --- Purkinje cell development in the mouse --- p.19 / Chapter 1.2.1 --- Embryonic development of mouse cerebellum --- p.19 / Chapter 1.2.2 --- Postnatal development of mouse cerebellum --- p.21 / Chapter 1.3 --- Degeneration of Purkinje cell leads to spinocerebellar ataxia --- p.22 / Chapter 1.4 --- LIM-homeodomain genes Lhx1 and Lhx5 --- p.24 / Chapter 1.4.1 --- LIM-homeodomain --- p.24 / Chapter 1.4.2 --- Lhx1 and Lhx5 are crucial to Purkinje cell differentiation --- p.25 / Chapter 1.5 --- Hypothesis, aim and strategy of the study --- p.26 / Chapter Chapter 2 --- Generation of Lhx5 conditional knockout allele in the mouse --- p.31 / Chapter 2.1 --- Chapter summary --- p.31 / Chapter 2.2 --- Introduction --- p.32 / Chapter 2.3 --- Materials and methods --- p.35 / Chapter 2.3.1 --- Materials --- p.35 / Chapter 2.3.2 --- Construction of Lhx5-conditional targeting vector by recombineering --- p.39 / Chapter 2.3.3 --- Gene targeting in mouse embryonic stem cells --- p.53 / Chapter 2.3.4 --- Generation of Lhx5 CKO mouse --- p.62 / Chapter 2.3.5 --- Histological examination of Lhx5 CKO mouse brain --- p.63 / Chapter 2.4 --- Results --- p.64 / Chapter 2.4.1 --- Generation of Lhx5 conditional targeting construct --- p.64 / Chapter 2.4.2 --- Screening of targeted ES cell clones --- p.64 / Chapter 2.4.3 --- Karyotyping --- p.65 / Chapter 2.4.4 --- Generation of chimeric mice and maintenance of Lhx5 CKO mice --- p.66 / Chapter 2.4.5 --- Histological examination of Lhx5 recombined null mutant mouse --- p.67 / Chapter 2.4.6 --- Gross anatomical examination of Lhx5 recombined null mutant mouse --- p.69 / Chapter 2.5 --- Discussion --- p.71 / Chapter Chapter 3 --- Generation and characterization of Pcp2-CreER[superscript T]² transgenic mouse --- p.75 / Chapter 3.1 --- Chapter summary --- p.75 / Chapter 3.2 --- Introduction --- p.76 / Chapter 3.3 --- Materials and methods --- p.79 / Chapter 3.3.1 --- Materials --- p.79 / Chapter 3.3.2 --- Construction of pPcp2-IRES-CreER[superscript T]²-FRT-Kan-FRT --- p.81 / Chapter 3.3.3 --- Generation of BAC-Pcp2-IRES-CreER[superscript T]² transgene --- p.85 / Chapter 3.3.4 --- Generation of Pcp2-CreER[superscript T]² transgenic mice --- p.90 / Chapter 3.3.5 --- Characterization of Pcp2-CreER[superscript T]² transgenic mice --- p.91 / Chapter 3.4 --- Results --- p.93 / Chapter 3.4.1 --- Construction of BAC-Pcp2-IRES-CreER[superscript T]² --- p.93 / Chapter 3.4.2 --- Production of Pcp2-CreER[superscript T]² transgenic mice --- p.93 / Chapter 3.4.3 --- Expression of Cre recombinase in Pcp2-CreER[superscript T]² transgenic mice --- p.93 / Chapter 3.4.4 --- Histological examination of Pcp2-CreER[superscript T]² transgenic mice --- p.97 / Chapter 3.4.5 --- Behavioral test of Pcp2-CreER[superscript T]² transgenic mice by rotarod --- p.98 / Chapter 3.5 --- Discussion --- p.100 / Chapter Chapter 4 --- Characterization of Lhx1/5 double conditional knockout mouse --- p.103 / Chapter 4.1 --- Chapter summary --- p.103 / Chapter 4.2 --- Introduction --- p.104 / Chapter 4.3 --- Materials and methods --- p.106 / Chapter 4.3.1 --- Mouse strain --- p.106 / Chapter 4.3.2 --- Behavioral tests --- p.106 / Chapter 4.3.3 --- Histological examination of cerebellum --- p.107 / Chapter 4.3.4 --- CreER[superscript T]² induction by tamoxifen --- p.108 / Chapter 4.3.5 --- Gene expression profiling using microarray --- p.109 / Chapter 4.3.6 --- Transmission electron microscopy --- p.110 / Chapter 4.3.7 --- Statistical analysis --- p.111 / Chapter 4.4 --- Results --- p.112 / Chapter 4.4.1 --- Early postnatal developmental delay in female DKO mutant --- p.112 / Chapter 4.4.2 --- Lhx1/5 DKO mutants displayed significant motor deficit --- p.114 / Chapter 4.4.3 --- Abnormal Purkinje cell dendritic arborization in the adult Lhx1/5 DKO mutant mouse --- p.117 / Chapter 4.4.4 --- Reduction in the number of synaptic vesicles in the adult Lhx1/5 DKO mutant --- p.119 / Chapter 4.4.5 --- Abnormal Purkinje cell dendrite development in the Lhx1/5 DKO mutant mouse --- p.120 / Chapter 4.4.6 --- Lhx1/5 were not required for the maintenance of developed Purkinje cell dendrite --- p.122 / Chapter 4.4.7 --- Comparison of gene expression profiles in the Lhx1/5 DKO mutant and control --- p.128 / Chapter 4.5 --- Discussion --- p.130 / Chapter Chapter 5 --- Foxp4 - a potential interacting partner of Lhx1/5 --- p.137 / Chapter 5.1 --- Chapter summary --- p.137 / Chapter 5.2 --- Introduction --- p.138 / Chapter 5.3 --- Materials and methods --- p.139 / Chapter 5.3.1 --- Co-immunoprecipitation --- p.139 / Chapter 5.3.2 --- Foxp4 expression pattern and knockdown in cerebellar slice culture --- p.140 / Chapter 5.3.3 --- Generation of Foxp4 CKO mouse --- p.146 / Chapter 5.4 --- Results --- p.148 / Chapter 5.4.1 --- Lhx1 and Lhx5 physically interacted with Foxp4 --- p.148 / Chapter 5.4.2 --- Foxp4 expression during mouse cerebellum development --- p.150 / Chapter 5.4.3 --- Effective gene silencing by siRNA in cerebellar slice culture --- p.151 / Chapter 5.4.4 --- Silencing gene expression of Foxp4 at P5 exerted no observable effect on Purkinje cell survival or differentiation --- p.154 / Chapter 5.4.5 --- Developed Purkinje cell dendritic arbors and associated Bergmann glial fibers were impaired when Foxp4 was knockdown at P10 --- p.157 / Chapter 5.4.6 --- Generation of Foxp4 targeting construct and conditional knockout mouse --- p.159 / Chapter 5.4.7 --- Developmental delay of cerebellum in Foxp4 recombined homozygous mutants --- p.163 / Chapter 5.4.8 --- Normal cerebellum development in adult En1-Cre; Foxp4[superscript fx/fx] and Pax2-Cre; Foxp4[superscript fx/fx] mutants --- p.165 / Chapter 5.4.9 --- Purkinje cell-specific knockout of Foxp4 did not impair Purkinje cell maintenance, motor activity and learning --- p.167 / Chapter 5.5 --- Discussion --- p.171 / Chapter 5.6 --- Acknowledgements --- p.177 / Chapter Chapter 6 --- General discussion, future works and conclusion --- p.179 / Chapter 6.1 --- Evolutionary conserved function of Lhx1 and Lhx5 in neurons --- p.180 / Chapter 6.2 --- LHX1 and LHX5 in human diseases --- p.181 / Chapter 6.3 --- Transcription complex between LIM-homeodomain and forkhead domain proteins may be important in the cerebellum development --- p.182 / Chapter 6.4 --- Future works --- p.183 / Chapter 6.5 --- Conclusion --- p.186 / References --- p.187
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Brain-derived neurotrophic factor and endocannabinoid functions i GABAergic interneuron development /Berghuis, Paul, January 2007 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.
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Cortical influences upon the dive response of the muskrat (Ondatra zibethica)McCulloch, Paul Frederick January 1989 (has links)
Force dived animals undergo cardiovascular changes characterized by bradycardia, increased total peripheral resistance, and changes in blood flow distribution. Since these changes occur in decerebrated animals, the dive response must be a brainstem reflex. However, in voluntary dives, animals may show anticipatory bradycardia and may also adjust their cardiovascular responses according to anticipated dive duration, indicating suprabulbar influences upon dive responses.
Studies of heart rate using telemetry have shown that there can be substantial differences in the dive response of voluntarily and force dived animals. Furthermore, some animals show a "fear bradycardia" when trapped in a stressful situation, leading some researchers to suggest that bradycardia during forced submersion is an artifact of the stress of the situation.
Muskrats (Ondatra zibethica) were observed freely diving for food in an indoor tank using a video camera and VCR unit. EKG was telemetered from the animals and recorded on the audio channel of the VCR tape. Heart rate responses to voluntary dives were analyzed and compared with those from escape and forced dives. Heart rate responses were also recorded from decorticate and sham operated muskrats to elucidate the role that the cerebral cortex plays in the dive response. In all types of dives, muskrats exhibited a rapid and large bradycardia upon submergence (heart rate declined by greater than 55% of the predive heart rate). Obviously diving bradycardia in the muskrat was not due to fear or stress, but occurred as a response to submersion per se. There was no evidence of post-dive tachycardia or anticipatory immersion bradycardia. Disturbing the animal in a non-diving situation resulted in only a 13% decrease in heart rate.
In intact animals voluntary, escape, and forced submergence resulted in progressively greater decreases in heart rate. Heart rate fell by 56% in voluntary dives, 65% in escape dives, and 73% in forced dives. Intensification of the bradycardia to a lower heart rate than that seen in voluntary dives was mediated by the cerebral cortex, as heart rate in decorticate muskrats in escape and forced dives did not fall below that seen in voluntary dives. This indicates that the final adjustment of dive heart rate is dependent upon an intact cerebral cortex. However, in decorticate muskrats there appeared to be a recovery of cortical function, as intensification of bradycardia in forced dives was dependent upon the time that had elapsed after surgery. This study shows that there is a cortical influence upon the cardiovascular system during diving. It also indicates that in experiments with unanesthetized animals, the degree of stress of the situation must be taken into account, as this may affect physiological responses. / Science, Faculty of / Zoology, Department of / Graduate
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Role of Tbr2 in intermediate progenitors during cortical neurogenesisVasistha, Navneet A. January 2013 (has links)
During embryonic development neurons of the cerebral cortex are generated from various progenitor cells that have progressively restricted fate. Understanding the multiple regulatory pathways that regulate the cell cycle kinetics and the identity of neurons is crucial to comprehend the etiology of severe developmental defects such as microcephaly and polymicrogyria and also the evolutionary expansion of the mammalian cerebral cortex. Intermediate progenitors (IPCs) express the transcription factor Tbr2 (a T-box gene) and deletion of this gene causes a decrease in brain size and cortical thickness. However, little is known about the molecular mechanisms regulating behavior of IPCs. In this thesis, I studied the molecular mechanisms regulating cell division and cell fate choices in IPCs using an overexpression system. I show that Tbr2 controls the expression of key genes such as Cdk4, Aspm and Wnt5a by directly binding to upstream regulatory sequences. These downstream targets could explain the role played by Tbr2 in cell cycle, spindle assembly and Wnt signaling in intermediate progenitors. The interaction with Aspm also suggests a possible mechanism of self-renewal of IPCs leading to an expanded generation of cortical neurons and ultimately an increased cortical size. While the role of IPCs in cortical neurogenesis is undisputed, it is widely believed that they contribute only towards supragranular layers. Using a knock-in transgenic mouse line (Tbr2<sup>Cre</sup>), I show that IPCs provide glutamatergic neurons (but not GABAergic neurons or GFAP+ astrocytes) towards all cortical layers in a significant proportion (20-40%). I also show that clonally generated neurons disperse within tangential dimension across the cortex significantly closer (142.1 ± 76.8 µm) than unrelated ones (294.9 ± 105.4 µm) though within the confines of a cortical column (300-600 µm). Finally, I describe the similarity in the germinal zones of a large-brained gyrencephalic rodent, agouti and a lissencephalic primate, marmoset. Both these species show similar germinal zone cytoarchitecture and distribution of various progenitors. Further, the number of IPCs is grossly expanded thus demonstrating the conserved role of IPCs in cortical expansion regardless of the folding status of the cortex in these two species.
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Large-Scale Networks in the Human Brain revealed by Functional Connectivity MRIKrienen, Fenna Marie 10 October 2015 (has links)
The human brain is composed of distributed networks that connect a disproportionately large neocortex to the brainstem, cerebellum and other subcortical structures. New methods for analyzing non-invasive imaging data have begun to reveal new insights into human brain organization. These methods permit characterization of functional interactions within and across brain networks, and allow us to appreciate points of departure between the human brain and non-human primates. / Psychology
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Snf2l Regulates Foxg1 Expression to Control Cortical Progenitor Cell Proliferation and DifferentiationMcGregor, Chelsea P. 05 September 2012 (has links)
Over the past five years the role of epigenetic modifiers in brain development has become increasingly evident. In this regard, Snf2l, a homolog of the chromatin remodeling protein ISWI, was shown to have enriched expression in the brain and be important for neuronal differentiation. Mice lacking functional Snf2l have hypercellularity of the cerebral cortex due to increased cell cycle re-entry. In this thesis I demonstrate the effects of Snf2l-ablation on cortical progenitor cells including increased proliferation and cell cycle deregulation, the consequence of which is a delay in neuronal migration and altered numbers of mature cortical neurons. This phenotype arises from increased expression of Foxg1, a winged-helix repressor expressed in the forebrain and anterior optic vesicle. Moreover, genetically reducing its overexpression rescues the Snf2l-ablated phenotype. Snf2l is bound directly to a promoter region of Foxg1 suggesting that it acts as a repressive regulator in vivo and is an important factor in forebrain differentiation.
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Cortical and thalamic innervation of striatumDoig, Natalie M. January 2012 (has links)
The basal ganglia are a collection of sub-cortical nuclei involved in the execution of a range of motor and cognitive behaviours. The striatum is the input nucleus of the basal ganglia, receiving major excitatory innervation from the cerebral cortex and intralaminar thalamic nuclei. The main target of these two pathways are the principal striatal neurons, the medium-sized spiny neurons (MSNs), which are subdivided based on their axonal targets and the expression of molecular markers. Direct pathway neurons project to the output nuclei of the basal ganglia and express the D, dopamine receptor subtype, whereas indirect pathway MSNs project to the output nuclei via the globus pallidus, and express the D2 receptor. The striatum also contains interneurons that are essential in processing information within striatum; the cholinergic interneuron is of particular interest due to its role in reward-related behaviour. The aim of this study was to examine the cortical and thalamic innervation of subtypes of striatal neurons. To examine whether the cortical or thalamic afferents selectively innervate direct or indirect pathway neurons, transgenic mice expressing GFP under either the D, or D2 receptor promoter were used. Striatal sections from these mice were immunostained to reveal the GFP and selective markers of the cortical and thalamic afferents, VGluTI and VGluT2, respectively. A quantitative electron microscopic examination ofsynaptic connectivity was carried out. The results indicate that there is no selectivity of either the cortical or thalamic pathway for D, or D2 expressing MSNs. Thus both direct and indirect pathway MSNs are involved in the processing of both cortical and thalamic information The cortical and thalamic innervation to cholinergic interneurons was also examined. Stimulation of cortex and thalamus in vivo in anaesthetised rats resulted in short-latency excitatory responses in identified cholinergic interneurons, indicative of monosynaptic connections. After recording, cholinergic interneurons were filled with neurobiotin. The synaptic innervation from cortex and thalamus was then examined in two individual, electrophysiologically characterised, and neurochemically identified cholinergic interneurons. One neuron received input from both cortex and thalamus, whereas the other neuron received input from the thalamus only. These results provide anatomical and physiological data illustrating how the excitatory inputs to striatum innervate cholinergic interneurons.
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Spatiotemporal patterns of neural fields in a spherical cortex with general connectivityUnknown Date (has links)
The human brain consists of billions of neurons and these neurons pool together
in groups at different scales. On one hand, these neural entities tend to behave
as single units and on the other hand show collective macroscopic patterns of activity.
The neural units communicate with each other and process information over time.
This communication is through small electrical impulses which at the macroscopic
scale are measurable as brain waves. The electric field that is produced collectively
by macroscopic groups of neurons within the brain can be measured on the surface
of the skull via a brain imaging modality called Electroencephalography (EEG). The
brain as a neural system has variant connection topology, in which an area might not
only be connected to its adjacent neighbors homogeneously but also distant areas can
directly transfer brain activity [16]. Timing of these brain activity communications
between different neural units bring up overall emerging spatiotemporal patterns.
The dynamics of these patterns and formation of neural activities in cortical surface
is influenced by the presence of long-range connections between heterogeneous neural
units. Brain activity at large-scale is thought to be involved in the information processing
and the implementation of cognitive functions of the brain. This research
aims to determine how the spatiotemporal pattern formation phenomena in the brain
depend on its connection topology. This connection topology consists of homogeneous
connections in local cortical areas alongside the couplings between distant functional
units as heterogeneous connections. Homogeneous connectivity or synaptic weight
distribution representing the large-scale anatomy of cortex is assumed to depend on
the Euclidean distance between interacting neural units. Altering characteristics of
inhomogeneous pathways as control parameters guide the brain pattern formation
through phase transitions at critical points. In this research, linear stability analysis
is applied to a macroscopic neural field in a one-dimensional circular and a twodimensional
spherical model of the brain in order to find destabilization mechanism
and subsequently emerging patterns. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection
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An investigation into the roles of Talpid3 and primary cilia in the developing brainBashford, Andrew January 2015 (has links)
The developing brain requires an intricate network of signals to direct proliferation, differentiation and cell fate decisions. Primary cilia are vital organelles with an emerging role regulating several major signalling cascades, in particular the Hedgehog pathway. Talpid3 (Ta3) is 166.7 kD protein found at the distal tip of centrioles. It has been shown to interact with a number of key centriolar proteins and is essential for the formation of primary cilia. A recent mouse model has been designed to conditionally target the highly conserved coiled-coil domain of Ta3 using the Cre/loxP system. This project uncovers the role of Ta3 in the developing brain. It characterises in detail the phenotype of mice with conditional loss of Ta3 in the central nervous system using the Nestin-Cre deleter strain. Morphological and histological analyses demonstrate that significant defects occur postnatally with mice developing severe ataxia and hydrocephaly. Immunohistochemical techniques further characterise the distinct phenotypes of three key brain regions including the cerebellum, cortex and hippocampus. Ta3fl/fl;NesCre mutant mice exhibit defects in the proliferation, organisation, morphology and migration of both neuronal and glial cells. We have shown the mechanistic cause to be the result of widespread loss of primary cilia and a concomitant disruption in the transduction of the Hedgehog signalling pathway. The neural roles of Ta3 are explored further through the optimisation of an in vitro neurosphere system to culture postnatal hippocampal progenitors. The use of a tamoxifen inducible strain allows the timely recombination of Ta3 to study its role in a controlled environment. The cultured cells recapitulate many of the in vivo defects showing loss of primary cilia and reduced migration. Finally, characterisation of the phenotypes seen in the Ta3fl/fl;NesCre mice were shown to resemble neurological traits seen in human conditions with loss of Primary cilia, known as ‘human ciliopathies’. Through clinical collaboration this project demonstrated a human ciliopathy case of Joubert Syndrome with compound heterozygous mutations in TA3. This presents the Ta3fl/fl;NesCre mutant mice as a valuable model system to study a rare but clinically relevant condition.
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