The superior neocortex ratios in primates and their distinctive relationship with sociality among terrestrial mammals are well documented. However, there has been an absence of research into relative neocortex size, its evolution and correlates in marine mammals, such as cetaceans (dolphins, porpoises and whales). This study uses the advanced radiological techniques of computed tomography and magnetic resonance imaging to establish neocortex ratios in dolphins and to re-assess these values for humans. It was found that freezing and defrosting did not significantly alter the neocortex ratios of dolphins and thus extra material as included in the analysis. Furthermore, equations for the estimation of neocortex ratios from eT and MRI have been applied to the cranial volumes calculated for 19 toothed whale species, in order to extend the range of analysis. Using these techniques, it appears that dolphin neocortex ratios are higher than those of other mammals, except for primates. A notable finding is that dolphin values lie between human and other primates and are closer to human ratios at 4.1, than to non-human ratios reaching 3.2~ (Dunbar, 1992). The highest delphinid neocortex ratio from MRI was 3.94 for common dolphins, while the highest estimated neocortex ratio was at 3.95 for killer whales. To establish the correlates of such high neocortex ratios in dolphins, their scores were related to variables representing foraging ecology, sound and sociality. Although delphinid neocortex ratios do not appear to be related to foraging variables, they are significantly related with sound and sociality variables. Of these relationships, the most substantial finding exists with respect to the relationship of delphinid neocortex ratios and their mean group size. The capacity to predict group size from relative neocortex size has not been noted in non-primate species, and has formed the basis for current theories of social intelligence and mental evolution. The findings of this study are therefore of considerable interest and may have substantial implications. These may impact on current theories of primate-human mental evolution and therefore it is strongly recommended that the mental capacities of other mammals, such as dolphins, be examined in greater detail to support or refute these claims. / Thesis (Ph.D.)-University of Natal, Pietermaritzburg, 1998.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 7, 2008). Includes bibliographical references.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Centre for Neuroscience. Title from pdf file main screen (viewed on October 31, 2009). Includes bibliographical references.

L’espèce humaine a développé des fonctions cognitives et des capacités d’interactions sociales très élaborées. La structure la plus importante pour ces fonctions est le néocortex. Une de ses caractéristiques majeures est qu’il a subi une forte expansion et un changement significatif de structure et de fonction durant l’évolution. Les mécanismes moléculaires et cellulaires sous-jacents à cette évolution restent peu connus. Un des éléments clefs semble être la modification de programmes neurodéveloppementaux spécifiques, en particulier au cours de la vie embryonnaire.<p>Durant ce projet, nous avons identifié et caractérisé de nouveaux gènes potentiellement impliqués dans le développement et l’évolution du cortex cérébral humain, par l’analyse du transcriptome du cerveau humain en développement, croisée à des techniques d’analyse computationnelle. Nous avons caractérisé le profil d’expression de « Human Accelerated Region 1 » (HAR1), un gène d’évolution accélérée dans la lignée humaine exprimé dans le cortex cérébral humain en développement. D’autre part, par l’analyse du transcriptome de régions spécifiques du cortex humain en développement, couplée à des analyses computationnelles, nous avons identifié une série de gènes présentant une combinaison unique de profil d’expression et d’évolution spécifiquement humains. Ces gènes pourraient constituer une partie importante des programmes génétiques impliqués dans le développement et l'évolution du cortex dans notre espèce.<p>L’étude approfondie de leurs profils d’expression et de leur fonction pourraient nous permettre de mieux comprendre les mécanismes moléculaires et cellulaires sous-jacents à l’évolution du cortex cérébral humain.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

No description available.

The human neocortex is a highly sophisticated and organized brain structure that is thought to mediate some of the most complex cognitive functions in humans including language and abstract thought. As such, environmental and genetic insults to its normal structure or function can result in devastating neurological conditions including severe epilepsy and intellectual disability. Malformations of cortical development are an increasing collection of disorders that cause neocortical abnormalities due to impaired developmental processes. One recently identified disorder in this class is a thin lissencephaly variant (TLIS) associated with several mutations in the C-terminus death domain of the caspase-2 activation adaptor CRADD (also known as RAIDD). Beyond this, little is known about the mechanism underlying TLIS pathophysiology despite an increasing number of identified individuals suffering from it. In order to better understand this disorder, as well as the normal developmental mechanisms that are impaired in its pathogenesis, I have developed and characterized three murine models by introducing one of a number of different genetic perturbations associated with TLIS. These animal models show behavioral and biochemical abnormalities similar to those seen in human TLIS subjects. Focusing future studies on the developmental processes that underlie differences seen in these mouse models could greatly inform understanding of disease mechanism in humans and assist in the development in therapeutic interventions. My work presented in this dissertation thus effectively establishes a translationally relevant animal model of TLIS.

The human brain relies on the complex interactions of distinct brain regions to support cognitive processes. The interplay between the hippocampus and neocortical regions plays a key role in the formation, storage, and retrieval of long-term episodic memories. Oscillatory activities during sleep are a fundamental mechanism that binds distributed neuronal networks into functionally coherent ensembles. However, the large-scale hippocampal-neocortical oscillatory mechanisms that support flexible modulation of long-term memory remain poorly understood. Furthermore, alterations to physiologic spatiotemporal patterns that are essential for intact memory function can result in pathophysiology in brain disorders such as focal epilepsy. Investigating how epileptic network activity disrupts connectivity in distributed networks and the organization of oscillatory activity are additional crucial areas that require further research. Our experiments on rodents and human patients with epilepsy have provided valuable insights into these mechanisms. In rodents, we used high-density microelectrode arrays in tandem with hippocampal probes to analyze intracranial electroencephalography (iEEG) from multiple cortical regions and the hippocampus. We identified key hippocampal-cortical oscillatory biomarkers that were differentially coordinated based on the age, strength, and type of memory. We also analyzed iEEG from patients with focal epilepsy and demonstrated how individualized pattern of pathologic-physiologic coupling can disrupt large-scale memory circuits. Our findings may offer new opportunities for therapies aimed at addressing distributed network dysfunction in various neuropsychiatric disorders.

Comprised of six distinct layers, the neocortex is a key brain structure for many of our advanced cognitive abilities, ranging from sensation to decision making to movement. Each layer contains distinct cell types differing in their genes, biophysical properties, and connectivity with other parts of the brain. Yet how these diverse cortical layers and cell types contribute to any given behavior remains unresolved. Because sensory cortical areas have stereotyped anatomies and the six cortical layer organization is highly conserved across all mammals, understanding computations in one cortical area, such as the mouse barrel cortex within the primary somatosensory cortex, may inform us of computations being performed by similar microcircuits across the neocortex. This thesis is an investigation of cortical circuit function as it pertains to (1) distinct functional role of cortical layers in sensory discrimination, (2) increased cortical connectivity enhancing sensation, (3) a cautionary tale of selecting appropriate transgenic mouse lines for in vivo manipulations, (4) and the role of proprioception in the establishment of long-term visuospatial memory. Investigating layer-specific function first requires a cortex-dependent task. Yet, despite our extensive understanding of cortical anatomy and physiology, the contributions of different cortical layers to behaviors remain unknown. We developed a two-alternative forced choice paradigm in which head-fixed mice use a single whisker to either discriminate textures of parametrically varied roughness or detect the same textured surfaces. Lesioning barrel cortex revealed that texture discrimination, but not detection, was cortex-dependent. Paralyzing the whisker pad demonstrated that passive can rival active perception and cortical dependence is not movement-related. Transgenic Cre lines were used to target inhibitory opsins to excitatory cortical neurons of specific layers for selective perturbations. Discrimination required all layers, but deep layers (layers 5/6) were critical for accumulation of sensory evidence whereas superficial layers (layers 2-4) appeared to provide top-down motor input. This thesis shows that superficial layers contextually interpret sensory evidence to modify the deep layer output in behaviorally appropriate ways. Having identified distinct functional roles of deep and superficial layers through perturbation experiments, we next sought to enhance texture task performance by selectively activating texture-encoding neurons. However, given that all layers are involved in the task and the technical difficulties of targeting stimulus-selective cells, we turned to humanized mouse model (SRGAP2C) that exhibits increased local and long-range cortico-cortical connections and increased response selectivity to whisker stimulations in layer 2/3 pyramidal neurons in the barrel cortex. This thesis demonstrates that the increased cortico-cortical connectivity not only improved sensory coding accuracy in SRGAP2C mice, but the humanized animals trained on the texture discrimination task displayed increased learning rate and were more likely to learn the task compared to control. Next, we provide a cautionary tale of selecting appropriate mouse lines for in vivo experiments. Advances in optogenetics and transgenic Cre mouse lines enable us to probe the function of genetically defined neuronal populations, but transgene expression can adversely affect cell health and cause neural and behavioral abnormalities. We discovered learning impairments specific to cortex-dependent sensory discrimination behaviors in Emx1-Cre animals that express inhibitory opsins in excitatory cortical neurons. We suggest Nex1-Cre line as a more reliable and robust alternative to Emx1-Cre animals. The thesis highlights the importance of characterizing and selecting appropriate transgenic lines for in vivo optogenetic experiments.  In addition to touch, the primary somatosensory cortex processes other tactile information including temperature, pain, and proprioception. Creating a spatially accurate representation of the visual world requires transforming spatially inaccurate visual information coming from a constantly moving retina into a representation that can be used for accurate perception and action. This thesis shows that the dysgranular zone, the proprioceptive region of the primary somatosensory cortex, is required to establish long-term visuospatial memory.

Die Erweiterung des grundlegenden Verständnisses der molekularen Mechanismen der Entwicklung, Organisation und Funktion des Neokortex ist ein Schlüssel zur Erforschung von Entwicklungsstörungen des Gehirns und zur Erarbeitung neuer Therapieansätze. Hier untersuchten wir die molekularen Mechanismen stromabwärts von Transkriptionsfaktoren der Neurod-Familie in der neokortikalen Entwicklung der Maus. Neurod1, Neurod2 und Neurod6 sind zentrale Regulatoren der neuronalen Differenzierung, Spezifikation und Axonführung. In dieser Arbeit zeigen wir, dass Neurod-Transkriptionsfaktoren über ein Zwischenmolekül den Tbr2-Transkriptionsfaktor unterdrücken, um eine ordnungsgemäße neuronale Migration und Differenzierung sicherzustellen. Die verlängerte ektopische Tbr2-Expression stört die neuronale Migration, Somagröße und dendritische Verzweigung in embryonalen und postnatalen Perioden. Wir untersuchen den genetischen Crosstalk zwischen Neurod1/2/3- und WWP1/2/miR-140-Wegen zu ihrem gemeinsamen nachgeschalteten Ziel Tbr2 und zeigten, dass diese Wege unabhängig voneinander auf Tbr2 konvergieren. Wir identifizieren neue nachgeschaltete Ziele von Neurod-Transkriptionsfaktoren wie Kcnq3, Bhlhe22 und Prdm8 und demonstrieren ihre entscheidende Rolle bei der richtigen Corpus Callosum-Etablierung. Darüber hinaus wird in dieser Forschung ein In-vitro-System zur Untersuchung der Callosom-Axon-Führung entwickelt und etabliert. Wir stellen fest, dass die Sh3gl2-Expression unter der Kontrolle von Neurod-Transkriptionsfaktoren steht und die Eliminierung von Sh3gl2 zu einer verzögerten Bestimmung des Zellschicksals führt. Wir nehmen an, dass die beeinträchtigte Sh3gl2-Expression in Neurod2/6 dKO- und Neurod1/2/6 tKO-Mutanten die Clathrin-unabhängige Endozytose und die anschließende Internalisierung von Membranrezeptoren stört, was zu einer Störung der Cortex-Zytoarchitektur führt. / Expanding the fundamental understanding of the molecular mechanisms of neocortex development, organization, and function is a key to investigating brain developmental disorders and elaborating new therapeutic approaches. Here, we studied the molecular mechanisms downstream of Neurod family transcription factors in mouse neocortical development. Neurod1, Neurod2, and Neurod6 are pivotal regulators of neuronal differentiation, specification, and axon guidance. In this study, we demonstrated that Neurod transcription factors via an intermediate molecule, repress the Tbr2 transcription factor to ensure proper neuronal migration and differentiation. The prolonged ectopic Tbr2 expression disrupts neuronal migration, soma size and dendritic branching in embryonic and postnatal periods. We investigated the genetic crosstalk between Neurod1/2/3 and WWP1/2/miR-140 pathways to their common downstream target Tbr2 and showed that these pathways converge on Tbr2 independently of each other. We identified new downstream targets of Neurod transcription factors such as Kcnq3, Bhlhe22, and Prdm8, and demonstrated their crucial role in the proper Corpus Callosum establishment. Moreover, an in-vitro system for investigation of the callosal axons guidance was developed and established in this research. We detected that Sh3gl2 expression is under Neurod transcription factors control and the Sh3gl2 elimination results in the delayed cell fate specification. We hypothesize that impaired Sh3gl2 expression in Neurod2/6 dKO and Neurod1/2/6 tKO mutants disrupts the clathrin- independent endocytosis and subsequent membrane receptors internalization, that leads to disturbance of cortex cytoarchitecture.

No description available.