Autor Markéta Popelová Název práce Software tool for modelling coding and processing of information in auditory cortex of mice Abstrakt Porozumění zpracovávání a kódování informací ve sluchové k·ře (AC) je stále ne- dostatečné. Z několika r·zných d·vod· by bylo užitečné mít výpočetní model AC, například z d·vodu vysvětlení, či ujasnění procesu kódování informací v AC. Prv- ním cílem této práce bylo vytvořit softwarový nástroj (simulátor SUSNOMAC), zaměřený na modelování AC. Druhým cílem bylo navrhnout výpočetní model AC s následujícími vlastnostmi: Izhikevich·v model neuronu, dlouhodobá plasticita ve formě Spike-timing-dependent plasticity (STDP), šestivrstvá architektura, pa- rametrizované typy neuron·, hustota neuron· a pravděpodobnost vzniku synapsí. Navržený model byl testován v desítkách experiment·, s r·znými sadami para- metr· a v r·zných velikostech (až 100 000 neuron· s takřka 21 milióny synapsí). Experimenty byly analyzovány a jejich výsledky srovnány s pozorováním skutečné AC. V práci popisujeme a analyzujeme několik zajímavých pozorování o aktivitě modelované sítě a vzniku tonotopického uspořádání AC. 1

Les processus d'apprentissage et de mémoire sont contrôlés par des circuits et éléments neuronaux spécifiques. De nombreuses études ont récemment mis en évidence que les circuits corticaux jouent un rôle important dans la régulation des comportements de peur, cependant, leurs caractéristiques anatomiques et fonctionnelles restent encore largement inconnues. Au cours de ma thèse, en utilisant des enregistrements unitaires et des approches optogénétiques chez la souris libre de se comporter, nous avons pu montrer que les interneurones inhibiteurs du cortex auditif et du cortex préfrontal médian forment un microcircuit désinhibiteur permettant respectivement l'acquisition et l'expression de la mémoire de peur conditionnée. Dans les deux cas, les interneurones parvalbuminergiques constituent l'élément central du circuit et sont inhibés de façon phasique. D’un point de vue fonctionnel, nous avons démontré que cette inhibition était associée à la désinhibition des neurones pyramidaux par un mécanisme de réduction de l'inhibition continue exercée par les interneurones parvalbuminergiques. Ainsi, les interneurones parvalbuminergiques peuvent contrôler temporellement l'excitabilité des neurones pyramidaux. En particulier, nous avons montré que l'acquisition de la mémoire de peur conditionnée dépend du recrutement d'un microcircuit désinhibiteur localisé dans le cortex auditif. En effet, au cours du conditionnement de peur, la présentation du choc électrique induit l'inhibition des interneurones parvalbuminergiques, ce qui a pour conséquence de désinhiber les neurones pyramidaux du cortex auditif et de permettre l’apprentissage du conditionnement de peur. Dans leur ensemble, ces données suggèrent que la désinhibition est un mécanisme important dans l'apprentissage et le traitement de l'information dans les circuits corticaux. Dans un second temps, nous avons montré que l'expression de la peur conditionnée requière l'inhibition phasique des interneurones parvalbuminergiques du cortex préfrontal médian. En effet, leur inhibition désinhibe les cellules pyramidales préfrontales et synchronise leur activité en réinitialisant les oscillations thêta locales. Ces résultats mettent en évidence deux mécanismes neuronaux complémentaires induits par les interneurones parvalbuminergiques qui coordonnent et organisent avec précision l’activité neuronale des neurones pyramidaux du cortex préfrontal pour contrôler l'expression de la peur conditionnée. Ensemble, nos données montrent que la désinhibition joue un rôle important dans les comportements de peur en permettant l’association entre des informations comportementalement pertinentes, en sélectionnant les éléments spécifiques du circuit et en orchestrant l'activité neuronale des cellules pyramidales. / Learning and memory processes are controlled by specific neuronal circuits and elements. Numerous recent reports highlighted the important role of cortical circuits in the regulation of fear behaviour, however, the anatomical and functional characteristics of their neuronal components remain largely unknown. During my thesis, we used single unit recordings and optogenetic manipulations of specific neuronal elements in behaving mice, to show that both the auditory cortex and the medial prefrontal cortex contain a disinhibitory microcircuit required respectively for the acquisition and the expression of conditioned fear memory. In both cases, parvalbumin-expressing interneurons constitute the central element of the circuit and are phasically inhibited during the presentation of the conditioned tone. From a functional point of view, we demonstrated that this inhibition induced the disinhibition of cortical pyramidal neurons by releasing the ongoing perisomatic inhibition mediated by parvalbumin-expressing interneurons onto pyramidal neurons. Thereby, this disinhibition allows the precise temporal regulation of pyramidal neurons excitability. In particular, we showed that the acquisition of associative fear memories depend on the recruitment of a disinhibitory microcircuit in the auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated inhibition of parvalbumin-expressing interneurons. Importantly, pharmacological or optogenetic blockade of pyramidal neuron disinhibition abolishes fear learning. Together, these data suggest that disinhibition is an important mechanism underlying learning and information processing in cortical circuits. Secondly, in the medial prefrontal cortex, we demonstrated that expression of fear behaviour is causally related to the phasic inhibition of prefrontal parvalbumin-expressing interneurons. Inhibition of parvalbumin-expressing interneuron activity disinhibits prefrontal pyramidal neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. These results identify two complementary neuronal mechanisms both mediated by prefrontal parvalbumin-expressing interneurons that precisely coordinate and enhance the neuronal efficiency of prefrontal pyramidal neurons to drive fear expression. Together these data highlighted the important role played by neuronal disinhibition in fear behaviour by binding behavioural relevant information, selecting specific circuit elements and orchestrating pyramidal neurons activity.

Humans’ perceptual experience of color is very different from what one might expect, given the light reaching the eye. Identical patterns of light are often perceived as different colors, and different patterns of light are often perceived as the same color. Even more strikingly, our perceptual experience is that hues are arranged circularly (with red similar to violet), even though single-wavelength lights giving rise to perceptions of red and violet are at opposite ends of the wavelength spectrum. The goal of this thesis is to understand how perceptual color space arises in the brain, focusing on the arrangement of hue. To do this, we use computational modeling to integrate findings about light, physiology of the visual system, and color representation in the brain. Recent experimental work shows that alongside spatially contiguous orientation preference maps, macaque primary visual cortex (V1) represents color in isolated patches, and within those patches hue appears to be spatially organized according to perceptual color space. We construct a model of the early visual system that develops based on natural input, and we demonstrate that several factors interact to prevent this first model from developing a realistic representation of hue. We show these factors as independent dimensions and relate them to problems the brain must be overcoming in building a representation of perceptual color space: physiological and environmental variabilities to which the brain is relatively insensitive (surprisingly, given the importance of input in driving development). We subsequently show that a model with a certain position on each dimension develops a hue representation matching the range and spatial organization found in macaque V1—the first time a model has done so. We also show that the realistic results are part of a spectrum of possible results, indicating other organizations of color and orientation that could be found in animals, depending on physiological and environmental factors. Finally, by analyzing how the models work, we hypothesize that well-accepted biological mechanisms such as adaptation, typically omitted from models of both luminance and color processing, can allow the models to overcome these variabilities, as the brain does. These results help understand how V1 can develop a stable, consistent representation of color despite variabilities in the underlying physiology and input statistics. This in turn suggests how the brain can build useful, stable representations in general based on visual experience, despite irrelevant variabilities in input and physiology. The resulting models form a platform to investigate various adult color visual phenomena, as well as to predict results of rearing experiments.

The relationship between structure, dynamics, and function of neural networks in nervous systems is still an open question in the neuroscience community. Nevertheless, for certain areas of the mammalian nervous system we do have sufficient data to impose constraints on the organisation of the network structure. One of these areas is the medial entorhinal cortex which contains cells with hexagonally repeating spatial receptive fields, called grid cells. Another intriguing property of entorhinal cortex and other cortical regions is a population oscillatory activity, with frequency in the theta (4-10 Hz) and gamma (30-100 Hz) range. This leads to a question, whether these oscillations are a common circuit mechanism that is functionally relevant and how the oscillatory activity interacts with the computation performed by grid cells. This thesis deals with applying the continuous attractor network theory to modelling of the microcircuit of layer II in the medial entorhinal cortex. Based on recent experimental evidence on connectivity between stellate cells, and fast spiking interneurons, I first develop a two-population spiking attractor network model that is capable of reproducing the activity of a population of grid cells in layer II. The network was implemented with exponential integrate and fire neurons that allowed me to address both the attractor states and the oscillatory activity in this region. Subsequently, I show that the network can produce theta-nested gamma oscillations with properties that are similar to the cross-frequency coupling observed in vivo and in vitro in entorhinal cortex, and that these theta-nested gamma oscillations can co-exist with grid-like receptive fields generated by the network. I also show that the connectivity inspired by anatomical evidence produces a number of directly testable predictions about the firing fields of interneurons in layer II of the medial entorhinal cortex. The excitatory-inhibitory attractor network, together with the theta-nested gamma oscillations, allowed me to explore potential relationships between nested gamma oscillations and grid field computations. I show, by varying the overall level of excitatory and inhibitory synaptic strengths, and levels of noise, in the network, that this relationship is complex, and not easily predictable. Specifically, I show that noise promotes generation of grid firing fields and theta-nested gamma oscillations by the model. I subsequently demonstrate that theta-nested gamma oscillations are dissociable from the grid field computations performed by the network. By changing the relative strengths of interactions between excitatory and inhibitory neurons in the network, the power and frequency of the gamma oscillations changes without disrupting the rate-coded grid field computations. Since grid cells have been suggested to be a part of the spatial cognitive circuit in the brain, these results have potential implications for several cognitive disorders, including autism and schizophrenia, as well as theories that propose a cognitive role for gamma oscillations.

Durant les dernières décennies, le système moteur a été largement étudié. Pourtant, bien des zones d'incertitudes persistent concernant d'une part la nature des circuits neuronaux de haut niveau impliqués dans l'émergence des sentiments d'intention ou de conscience motrice et d'autre part l'organisation des structures cérébrales de bas-niveau impliquées dans l'expression de ces sentiments. Il a été suggéré que le cortex pariétal et l'aire motrice supplémentaire pourraient jouer un rôle dans la génération des intentions motrices, alors que le cortex prémoteur pourrait plutôt sous-tendre la conscience du geste. Cela étant, les processus exacts implémentés dans chacune de ces régions, la façon dont elles interagissent fonctionnellement et la nature des signaux qu'elles échangent avec les structures sensorimotrices considérées de bas-niveau demeurent méconnus. Il est établi que ces structures bas-niveau, dont le cortex moteur primaire et le cervelet, contiennent des cartes sensorimotrices organisées de manière topographique. Cependant, l'organisation fine de cette topographie et la nature des interactions entre les différentes cartes restent à définir. Dans ce travail de thèse, j'ai utilisé la stimulation électrique directe chez des patients opérés de tumeurs et malformations cérébrales pour explorer la manière dont les multiples représentations motrices sont organisées et pour identifier les régions responsables de l'émergence des sentiments d'intention et de conscience motrice. J'ai alors pu montrer, en particulier, l'existence de cartes motrices multiples au sein des cortex moteur primaire et cérébelleux. Par ailleurs, j'ai pu identifier le rôle critique du cortex pariétal pour l'émergence du sentiment d'intention motrice et -sur la base de processus prédictifs- de la conscience d'agir. Par rapport à ce point, j'ai aussi pu mettre en évidence que le cortex prémoteur était impliqué, à travers un contrôle continu des prédictions pariétales, dans l'émergence d'une conscience d'agir non plus inférée mais véritable / During the last five decades, the motor system has been widely studied. Yet, little is known about the neural substrate of high-level aspects of movement such as intention and awareness and how these functions are related to low-level movement execution processes. It has been suggested that the parietal cortex and supplementary motor area are involved in generating motor intentions, while premotor cortex may play a role in the emergence of motor awareness. However, the precise mechanisms implemented within each of these areas, the way they interact functionally and the nature of the signals conveyed to primary sensory and motor regions is far from being understood. Furthermore, intention and awareness of movement are also influenced by peripheral information coming from the skin, muscles and joints, and this information must be integrated to produce smooth, accurate and coordinated motor actions. Cortical and subcortical structures such as the primary motor cortex and the cerebellum are known to contain motor maps thought to contribute to motor control, learning and plasticity, but the intrinsic organization of these maps and the nature of their reciprocal relations are still unknown. In this thesis I used Direct Electrical Stimulation in patients undergoing brain surgeries to investigate how multiple motor representations are organized and identify the regions responsible for the emergence of conscious motor intention and awareness. I showed, in particular, the existence of multiple efferent maps within the cerebellum and the precentral gyrus. Furthermore, I identified the critical role of the parietal cortex for the emergence of conscious intention and -based on predictive processes- motor awareness. I also provided evidence that the premotor cortex is involved in "checking" parietal estimations, thus leading to a sense of "veridical awareness"

Patienten mit Depression zeigen typischerweise eine Beeinträchtigung kognitiver Funktionen, vor allem im Bereich der exekutiven Funktionen. Als neuroanatomisches Korrelat konnte den exekutiven Funktionen der präfrontale Kortex zugeordnet werden. In den bisherigen bildgebenden Untersuchungen bei depressiven Patienten konnte vor allem eine Hypofrontalität festgestellt werden. Durch verschiedene neuropsychologische Tests konnten kognitive Defizite vor allem im visuell-räumlichen Arbeitsgedächtnis gezeigt werden. Als neuroanatomisches Korrelat konnte dem Arbeitsgedächtnis der DLPFC zugeordnet werden. Die bisher durchgeführten kombinierten Untersuchungen bei depressiven Patienten lieferten jedoch keine einheitlichen Ergebnisse. Mittelpunkt unserer Untersuchung war es deshalb mittels NIRS während der Durchführung eines Tests für das visuell-räumliche und das objektbezogene Arbeitsgedächtnis sowohl bei einer Patientengruppe mit unipolarer Depression als auch bei einer gesunden Kontrollgruppe die Aktivierungsmuster des präfrontalen Kortex zu ermitteln. Für den Zusammenhang zwischen der Hirnaktivierung und der Schwere der depressiven Erkrankung konnten keine signifikanten Korrelationen gezeigt werden. Dies spricht gegen den „state“-Charakter und für den „trait“-Charakter der Hypofrontalität bei einer depressiven Erkrankung. Die bezüglich der Verhaltensdaten gerechneten Varianzanalysen zeigten eine deutliche Schwierigkeitsabstufung zwischen den drei Bedingungen (OWM>VWM>KON). Der fehlende Interaktionseffekt Gruppe x Bedingung, also eine höhere Reaktionszeit der Patienten während allen Aufgaben und nicht nur während OWM und VWM deutet auf eine allgemeine Verlangsamung im Sinne einer psychomotorischen Verlangsamung hin und nicht wie erwartet auf ein besonderes Defizit im Bereich kognitiver Funktionen. Interaktionseffekte bei den bildgebenden Daten bei gleichzeitig fehlenden Interaktionsnachweisen bei den Verhaltensdaten deuten an, dass die funktionellen Daten unabhängig von den Verhaltensdaten interpretiert werden können. Ein kognitives Defizit für beide Komponenten des visuell-räumlichen Arbeitsgedächtnisses bei Patienten mit einer depressiven Erkrankung zeigt sich in unserer Untersuchung also weniger über die Verhaltensdaten als vielmehr über die verminderte Hirnaktivierung während OWM und VWM. Im Gruppenvergleich konnte in den ROI-Analysen für OWM und VWM wie erwartet ein spezieller Arbeitsgedächtniseffekt gezeigt werden, also eine höhere Aktivierung der Kontrollgruppe speziell für die Arbeitsgedächtnisaufgaben. Es wurde also insgesamt in unserer Untersuchung eine präfrontale Hypoaktivierung bei Patienten mit einer depressiven Erkrankung festgestellt. / Patients suffering from depression typically show an impairment of cognitive functions, especially concerning the executive functions. The pre-frontal cortex was determined to be the neuroanatomical correlate of the executive functions. In previous imaging examinations of patients suffering from depression, a hypofrontality was demonstrated. By using different neuropsychological tests, cognitive deficits, especially for the visual-spatial working memory, could be demonstrated. The DLPFC could be shown to be the neuroanatomical correlate of the working memory. The previous combined examinations of patients suffering from depression had, however, failed to show consistent results. The focus of our examination therefore was to detect the pattern of brain activation of patients with a unipolar depression and healthy controls during a visual-spatial (VWM) and visual-object (OWM) working memory task by using Near-infrared Spectroscopy. Significant correlations concerning the connnection between brain activation and the severity of the depressive disease could not be demonstrated. This favors the “trait”-character rather than the “state”-character of the hypofrontality of a depressive disease. The analyses of variance of the behavioral data showed a clear grading of the difficulties among the three conditions (OWM>VWM>KON). The missing effect of interaction group x condition, meaning higher reaction times of the patients during all tasks and not just during OWM and VWM, implies a general slowing down in terms of a psychomotoric slowing down and not – different from what we had expected- a special deficit in the area of the cognitive functions. The effects of interaction of the imaging data combined with the missing effects of the behavioral data imply that the functional data can be interpreted independently from the behavioral data. In our examination, the cognitive deficit for both components of the visual-spatial working memory of patients with a unipolar disease can be demonstrated to a lesser degree through the behavioral data than through the attenuated brain activation during OWM and VWM. As we expected, in the comparison of the groups a special effect for working memory could be demonstrated in the ROI-analyses for OWM and VWM, meaning a higher activation of the control group, especially for the working memory tasks. Therefore, in general, our examination demonstrated a prefrontal hypoactivation of patients suffering from a depressive disease.

Abstract (for Chapter 2) Objective: The aim was to test the hypothesis that the order is a significant phylogenetic grouping in terms of quantifiable gyrification indices. Method: The gyrification index (GI) was measured from serial sections of the brain of twenty five different mammalian species, representing the different orders i.e. primates, carnivores, artiodactyls and rodents. Image J analysis was used to measure the contours of the cerebral cortex and the GI was calculated using three different methods of analysis i.e. complete vs outer; gyral vs sulcal and outer vs inner surface contours. The measurements were then computed against the brain weights of each species within the order. Results: An increasing GI correlates with an increasing brain weight in all the mammalian orders. Each order has its own specific allometric patterns that are significantly different from the other orders examined. The artiodactyls were the mammals with the most gyrencephalic brains, these species being significantly more gyrencephalic than all other mammals when species of similar brain weights are compared. The North American beaver has an atypically lissencephalic brain for its size, differing from the trend for increased gyrencephaly found in the other rodent species examined. Conclusions: Our results show definite trends and patterns specific to each order. So it would seem that the order is a significant phylogenetic grouping in terms of this neural parameter, from which we can predict with a reasonable degree of certainty, the GI of any species of a particular order, if we know the brain weight. Abstract (for Chapter 3) The mammalian order has proven to be a significant phylogenetic grouping in terms of gyrification from which we can predict with a reasonable degree of certainty, the GI of any species of a particular order, if we know the brain weight. We have attempted in the present study to identify potential causes for gyrification at the class level by investigating relationships at the level of the order. It appears that clues to the extent and pattern of gyrification in the different mammalian orders might be related to the bones that constitute the braincase. The external surface areas of the bones of the cranial vault of seventeen different mammalian species were measured using a microscribe digitiser. These values were plotted against brain weight from which we could then calculate residual values, determining if there was more or less external cranial vault area than expected for the size of the brain. These residuals were then plotted against the gyrification indices determined in a previous study for the species examined. Results indicated that for the primates and artiodactyls the skull may potentially be considered as a limiting factor on the expansion of the cerebral cortex; however, the carnivore and rodent orders show conflicting results which suggest that the relative surface area of the skull appears to have no effect on the quantitative extent of gyrencephaly. These inconclusive findings suggest that causes contributing to the quantitative extent of gyrification across mammals may be multifactorial, and more parameters may need to be included in the analysis to arrive at an answer.

No condicionamento clássico de medo, os animais são treinados associando-se um estímulo neutro, por exemplo, som, contexto ou luz a um estímulo aversivo incondicionado, como um choque elétrico nas patas. Apos repetidos pareamentos, a presença do estímulo que inicialmente era neutro passa a eliciar uma resposta condicionada de medo no animal. O congelamento é a resposta mais proeminente dos animais expostos aos estímulos condicionados previamente pareados com choques nas patas, sendo freqüentemente utilizado como medida de medo condicionado (MC). Circuitos cerebrais independentes subjacentes a diferentes formas de memória, e, dentro de um determinado domínio de memória, o envolvimento de estruturas específicas pode depender do tipo de condicionamento se utilizando contexto ou explícito tais sinais leves ou som. Diversos relatos clínicos têm implicado o prejuízo do lobo temporal medial (LTM) com amnésia retrógrada. Embora muito tenha sido feito para desvendar os circuitos neurais subjacentes ao medo condicionado, utilizando contexto, som ou luz como estímulo condicionado (EC) o envolvimento do LTM nessas formas de condicionamento ainda não está claro. Para abordar esta questão foi avaliada a distribuição de Fos no LTM de ratos após a exposição a um contexto, um som ou luz, previamente emparelhado com choques nas patas. Vinte e quatro horas após as sessões de condicionamento, os animais foram colocados na mesma caixa experimental ou a um contexto distinto ou foram expostos ao som e luz sem receber choques nas patas. Diferença significativa na expressão de Fos foi determinada por análise de regiões do lobo temporal medial (córtex ectorrinal, perirrinal e entorrinal) e do hipocampo ventral. Os resultados comportamentais mostraram que houve congelamento nos três tipos de medo condicionado, mas o padrão de distribuição Fos foi diferente em ratos expostos a estímulos específicos ou contexto previamente emparelhado com choques nas patas. Apesar da saliente aquisição da resposta do medo se simular nas três condições, o achado mais saliente foi uma distribuição selectiva de Fos no córtex ectorrinal, perirrinal e entorrinal do grupo. Surpreendentemente, esses animais não mostraram significativa expressão Fos no hipocampo ventral. Isto sugere que o contexto e estímulos aversivos explícitos apresentam propriedades distintas de mapeamento ao de distribuição de Fos no circuito cortico-hipocampal cerebral. Estes resultados indicam que regiões corticais no LTM parecem ser críticas no armazenamento de informações contextuais, mas não de informações associadas a estímulos explícitos previamente pareados a choques nas patas. / Conditioned fear (CF) is one of the most frequently used animal models of associative memory to background or foreground stimuli. Independent brain circuits underlie different forms of memory, and, within a particular memory domain, the involvement of specific structures may depend upon the type of conditioning whether using context or explicit cues such light or tone. Several clinical reports have implicated the damage to the medial temporal lobe (MTL) with retrograde amnesia. Although much has been done to disclose the neural circuits underlying CF using context, tone or light as conditioned stimuli (CS) the involvemet of the MTL in these forms of conditioning is still unclear. To address this issue we assessed the Fos distribution in the MTL of rats following exposure to a context, a tone or a light previously paired with footshocks. Twenty-four hours later the conditioning sessions they were placed to the same chamber or to a distinct context and presented with tone or light only without any footshocks. Significant group differences in regional Fos expression were determined by analysis in regions of the medial temporal lobe (ectorhinal, perirhinal and entorhinal cortices) and the ventral hippocampus. The behavioral results showed comparable freezing in the three types of CF but the pattern of Fos distribution was distinct in rats exposed to specific cues or context previously paired with footshocks. Despite comparable acquisition of the conditioned fear response, the most remarkable finding was a selective distribution of Fos in the entorhinal, perirhinal and ectorhinal cortices of the MTL for context-CS groups. Remarkably, these animals did not show significant Fos expression in the ventral hippocampus. It is suggested that context and explicit stimuli endowed with aversive properties through conditioning cause distinct Fos brain mapping in the corticohippocampal circuitry. These results indicate that tasks requiring the association between context and an aversive stimulus depend on subregions of the MTL. Such findings suggested that cortical regions of the MTL appears to be critical for storing context but not explicit cue footshock associations.

The regulation of gene expression resulting in the formation of the mammalian cerebral cortex is tightly regulated by a group of transcription factors. The deletion of any one of these transcription factors results in numerous defects whose nature and severity depends on the role of the transcription factor in the regulation of complex gene regulatory networks involved in development. There is currently relatively little knowledge about the gene networks that these transcription factors control and how they exert their regulatory effects. The paired-box transcription factor Pax6 has been identified as a master regulator of gene networks involved in cortical development and its deletion results in numerous cortical defects such as an abnormally thin cortical plate and a vastly expanded proliferative zone. Previous work in our lab identified a list of candidate genes that are likely to be regulated by Pax6 in the developing cortex. Members of the Notch signalling pathway were potential Pax6 targets of particular interest since Notch signalling plays a crucial role in the maintenance of neural progenitor cells during development and consequently plays a critical role during corticogenesis. Our work aims to identify the regulatory relationship between Pax6 and Notch ligands Dll1 and Jag1 during cortical development. Analysis by flow cytometry and double labelling analysis of both gene and protein expression has provided insight into the relationship between Pax6 and Dll1 in progenitor cell subpopulations during cortical development. In situ hybridisation and qPCR results confirmed that loss of Pax6 causes loss of Dll1 expressing cells and downregulation of Jag1, indicating that both ligands are regulated by Pax6. Bioinformatic screening and analysis by luciferase assay suggests that Jag1 is a likely candidate to be a direct target of Pax6.

The response of a neuron encoding information about a sensory stimulus is influenced by the context in which that information is presented. In the primary visual cortex (area V1), neurons respond selectively to stimuli presented to a relatively constrained region of visual space known as the classical receptive field (CRF). These responses are influenced by stimuli in a much larger region of visual space known as the extra-classical receptive field (eCRF). In that they cannot directly evoke a response from the neuron, surround stimuli in the eCRF provide the context for the input to the CRF. Though the past few decades of research have revealed many details of the complex and nuanced interactions between the CRF and eCRF, the circuit mechanisms underlying these interactions are still unknown. In this thesis, we present a simple, novel cortical circuit model that can account for a surprisingly diverse array of eCRF properties. This model relies on extensive recurrent interactions between excitatory and inhibitory neurons, connectivity that is strongest between neurons with similar stimu- lus preferences, and an expansive input-output neuronal nonlinearity. There is substantial evidence for all of these features in V1. Through analytical and computational modeling techniques, we demonstrate how and why this circuit is able to account for such a comprehensive array of contextual modulations. In a linear network model, we demonstrate how surround suppression of both excitatory and inhibitory neurons is achieved through the selective amplification of spatially-periodic pat- terns of activity. This amplification relies on the network operating as an inhibition-stabilized network, a dynamic regime previously shown to account for the paradoxical decrease in in- hibition during surround suppression (Ozeki et al., 2009). With the addition of nonlinearity, effective connectivity strength scales with firing rate, and the network can transition be- tween different dynamic regimes as a function of input strength. By moving into and out of the inhibition-stabilized state, the model can reproduce a number of contrast-dependent changes in the eCRF without requiring any asymmetry in the intrinsic contrast-response properties of the cells. This same model also provides a biologically plausible mechanism for cortical normalization, an operation that has been shown to be ubiquitous in V1. Through a winner-take-all population response, we demonstrate how this network undergoes a strong reduction in trial-to-trial variability at stimulus onset. We also propose a novel mechanism for attentional modulation in visual cortex. We then go on to test several of the critical pre- dictions of the model using single unit electrophysiology. From these experiments, we find ample evidence for the spatially-periodic patterns of activity predicted by the model. Lastly, we show how this same circuit motif may underlie behavior in a higher cortical region, the lateral intraparietal area.