Executive functioning is a multidimensional concept encompassing higher-order adaptive abilities, such as judgment, decision-making, self-monitoring, planning, and emotional regulation. Disruption in executive functioning often results in devastating impairments in vitally-important areas of life, such as one's ability to hold employment and maintain social relationships. Executive functions have been associated primarily with the prefrontal cortex. However, the nature and degree of the association between frontal lobe damage and performance on executive functioning tests remains controversial. Research suggests that the association may vary based on the specific location of damage within the prefrontal cortex, as well as the used measure of executive functioning. Few investigations have systematically addressed these variables. The current study employed the lesion method to investigate the relationship between performance on a battery of executive functioning tests and damage to specific regions of the prefrontal cortex. Three groups of participants with lesions in one of the locations of interest [ventromedial prefrontal (VMPC, n = 14), dorsolateral prefrontal (DLPC, n = 14), and non-frontal (n = 18)] were administered the Delis-Kaplan Executive Function System (D-KEFS, 2001), a comprehensive battery of executive functioning tests. Results revealed no statistically-significant differences between group performances on the D-KEFS primary measures. However, a qualitative analysis of the results revealed several meaningful group differences. It appears that some relationship exists between frontal lobe damage, particularly in the DLPC, and decreased performance on several executive functioning tests but further research overcoming the methodological limitations of most existing literature on this topic is needed to clearly resolve this issue.

Previous research has indicated that the perirhinal cortex (PRh) and posterior parietal cortex (PPC) functionally interact to mediate crossmodal object representations in rats; however, it remains to be seen whether other cortical regions contribute to this cognitive function. The prefrontal cortex (PFC) has been widely implicated in crossmodal tasks and might underlie either a unified multimodal or amodal representation or comparison mechanism that allows for integration of object information across sensory modalities. The hippocampus (HPC) is also a strong candidate, with extensive polymodal inputs, and has been implicated in some aspects of object recognition. A series of lesion based experiments assessed the roles of HPC, PFC and PFC sub regions [medial prefrontal (mPFC) and orbitofrontal cortex (OFC)], revealing functional dissociations between these brain regions using two versions of crossmodal object recognition: 1. spontaneous crossmodal matching (CMM), which requires rats to compare between a stored tactile object representation and visually-presented objects to discriminate the novel and familiar stimuli; and 2. crossmodal object association (CMA), in which simultaneous pre-exposure to the tactile and visual elements of an object enhances CMM performance across long retention delays. Notably, while inclusive PFC lesions impaired both CMM and CMA tasks, selective OFC lesions disrupted only CMM, whereas selective mPFC damage did not impair performance on either task. Furthermore, there was no impact of HPC lesions on either CMM or CMA tasks. Thus, the PFC and the OFC play a selective role in crossmodal object recognition but the exact contributions and interactions of the regions will require further research to elucidate. / PDF Document / Natural Sciences and Engineering Research Council of Canada (NSERC)

Executive control is a vital cognitive function that facilitates the focussing and shifting of attention, planning and working towards a goal, ignoring distractions, and flexibly responding to novel situations. Disruptions to executive control are seen in many psychiatric and neurodegenerative disorders, as well as healthy ageing, which can be profoundly detrimental. Despite having many effective and well-validated methodologies for detecting and quantifying these deficits, there are very few treatments — pharmacological or otherwise — for ameliorating executive dysfunction. This lack of progress can partly be blamed on difficulties associated with identifying drugs that enhance cognition in preclinical research. The work in this thesis aimed to expand our understanding of executive dysfunction — as well as the tasks that measure it — in rats. In results presented in chapter three, middle-aged rats demonstrated impaired reversal learning on the standard attentional set-shifting task, but this was treatable with a novel drug targeting the N-methyl-D-aspartate receptor. The age impairments seen in this experiment were similar to those previously found in young rats with orbital prefrontal cortex (OFC) lesions. The results of chapter four expanded on this similarity to show that, along with reversal deficits, young OFC-lesioned rats are impaired at forming attentional sets when tested on a modified task. In chapter five, another modified set-shifting task revealed that middle-aged rats also suffer from impaired set-formation, but their reversal learning impairments only manifest before attentional set has been formed — not after. Finally, in chapter six, the putative cognitive enhancer modafinil was found to exacerbate middle-aged rats' reversal learning deficit, but it also enhanced their subsequent ability to form attentional set. These experiments reveal that modifying the rat attentional set-shifting task can sometimes make it a more effective tool for testing cognitive enhancers in preclinical settings.

Can the brain register the emotional valence of brief exposures of complex natural stimuli under conditions of forward and backward masking, and under conditions of attentional competition between foveal and peripheral stimuli? To address this question, three experiments were conducted. The first, a behavioural experiment, measured subjective valence of response (pleasant vs unpleasant) to test the perception of the valence of natural images in brief, masked exposures in a forward and backward masking paradigm. Images were chosen from the International Affective Picture System (IAPS) series. After correction for response bias, responses to the majority of target stimuli were concordant with the IAPS ratings at better than chance, even when the presence of the target was undetected. Using functional magnetic resonance imaging (fMRI), the effects of IAPS valence and stimulus category were objectively measured on nine regions of interest (ROIs) using the same strict temporal restrictions in a similar masking design. Evidence of affective processing close to or below conscious threshold was apparent in some of the ROIs. To further this line of enquiry, a second fMRI experiment mapping the same ROIs and using the same stimuli were presented in a foveal (‘attended’) peripheral (‘to-be-ignored’) paradigm (small image superimposed in the centre of a large image of the same category, but opposite valence) to investigate spatial parameters and limitations of attention. Results are interpreted as showing both valence and category specific effects of ‘to-be-ignored’ images in the periphery. These results are discussed in light of theories of the limitations of attentional capacity and the speed in which we process natural images, providing new evidence of the breadth of variety in the types of affective visual stimuli we are able to process close to the threshold of conscious perception.

As teorias mais influentes acerca do funcionamento do córtex pré-frontal (PFC) tomam essa estrutura como um córtex de associação e de integração de informações oriundas de outras estruturas nervosas. Isso implicaria na participação direta do PFC nos processos de memória operacional e em processo atencionais. Estudos hodológicos e neurofisiológicos sugerem, que o córtex orbitofrontal (OFC) seria responsável pela integração de informações de caráter sensorial, motivacional e afetivo, enquanto o córtex pré-frontal ventromedial (vmPFC) seria diretamente ligado ao OFC, tendo um papel crucial na codificação de estímulos emocionais oriundos da amígdala. Nesse contexto, é aceito que a integração das informações feita por essas estruturas seja essencial para o processo de tomada de decisões, uma vez que esse comportamento necessita de uma avaliação do ambiente em termos de comparações de situações novas a experiências prévias armazenadas na memória, assim como um balanço entre custos, benefícios e cálculo de possíveis valores da recompensa. Para testar essas hipóteses, ratos com danos seletivos no vmPFC foram submetidos testes de avaliação de ansiedade e medo condicionado no paradigma de teste e reteste no labirinto em cruz elevado (LCE), assim como a testes de memória de referência espacial e memória operacional no labirinto aquático de Morris. Outro grupo de animais teve matrizes de multi-eletrodos implantadas no OFC para a avaliação da atividade neuronal dessa estrutura em um teste envolvendo tomada de decisões, no qual devem escolher entre ganhar 1 pellet de chocolate imediatamente ou 4 pellets envolvendo atrasos variados. No teste no LCE, animais com lesão no vmPFC diferem dos animais controle por apresentarem uma diminuição do tempo de avaliação de risco sem apresentar alterações nos parâmetros que aferem memória, atividade locomotora e ansiedade. No teste de memória de referência espacial após treinamento extensivo de busca pela plataforma em um mesmo local no labirinto aquático, animais com lesão persistem no local quando se retira a plataforma (probe test). Já no teste de memória operacional, no qual a localização da plataforma é alterada diariamente, esses animais não diferem do grupo controle. Na tarefa envolvendo tomada de decisões, observou-se uma atividade eletrofisiológica de neurônios do OFC relacionada ao momento crítico no qual o animal deve realizar uma escolha. Em conjunto, esses resultados mostram que o vmPFC está relacionado à flexibilidade comportamental e tomada de decisões, possivelmente em conjunto com o OFC, cuja atividade neuronal sugere uma participação nos processos de tomada de decisões e de elaboração de estratégias / The most influential theories on the function of the prefrontal cortex (PFC) suggest that this structure is an association cortex, responsible for integration of information received from other parts of the brain. This would implicate in direct participation of the PFC in working memory and attentional processes. Given this context, hodological and neurophysiological studies suggest that the orbitofrontal cortex (OFC) would be responsible for the integration of sensory, motivational and affective aspects, while the ventromedial prefrontal cortex (vmPFC), which is directly connected to the OFC, would have a key role in encoding emotional stimuli from the amygdala. It is well accepted that the processing of these aspects of information is crucial for decision-making processes, given the fact that this expression of behavior requires an evaluation of the environment in terms of comparing novel situation to previous experiences, as well as processing the balance between costs, outcomes and reward values. In order to test these hypotheses, rats with selective lesions to the vmPFC were subjected to the elevated plus maze (EPM) to evaluate anxiety and conditioned fear in the test retest paradigm. Animal were also tested in a spatial reference memory and a working memory tasks in the Morris water maze. Another group of rats had multi-electrode arrays chronically implanted in the OFC for the evaluation of the neuronal activity during a decision-making task, in which the animals had to choose between a small reward of one chocolate pellet immediately and a large reward of four chocolate pellets after varying delays. The results of the EPM show that animals with lesion to the vmPFC differ from control animals by showing diminished time evaluating risk in the second exposure to the EPM, without damage to locomotor activity, memory and anxiety levels. In the reference spatial memory task in the water maze, after extensive training searching for the hidden platform in the same location, lesioned animals persisted searching for the platform in that particular location after it was removed (probe test). However, in the working memory task, in which the platform is presented in a different location each day, lesioned animals did not differ from control animals. In the decision-making task, differential electrophysiological activity in OFC neurons was observed, particularly in the moment of the task in which the animal was required to perform the choice between rewards. Together, these results suggest that the vmPFC is related to behavioral flexibility and decision-making, possibly acting together with the OFC, which neuronal activity suggests participation in decision-making processes

The prefrontal cortex (PFC) has long been thought to be the seat of social behaviours in mammals. Lesions of the orbitofrontal cortex (OFC), a subregion of the PFC, are known to cause social deficits in humans. Interestingly, social deficits are also seen in rats with OFC lesions. Rats that are deprived of peer play during development exhibit behaviour similar to OFC-ablated animals. Another subregion of the PFC, the medial prefrontal cortex (mPFC) is interconnected with the OFC. The mPFC and OFC have been shown to be reciprocally responsive to a variety of inuences, in terms of dendritic morphology. It was hypothesized that social experiences are necessary for the proper development of the OFC, and that, because of the interconnectivity, the mPFC would also be sensitive to social experience. The social condition in which juvenile rats were raised was manipulated, and the OFC and mPFC were shown to be differentially responsive to specific aspects of social experience. It was already known that OFC lesions produce specific social deficits, but the contribution of the mPFC to the production of social behaviour was unknown. To investigate the contribution of the mPFC to the performance of social behaviour, animals were given mPFC lesions, and their social play behaviour was quantified. mPFC-ablated animals had altered play patterns that were distinct from those seen in the OFC-ablated animals. It was concluded that the OFC and mPFC are differentially responsive to social stimuli during development, and that the OFC and mPFC make discrete contributions to the production of social behaviour. The results were interpreted in an evolutionary context. / x, 93 leaves : ill. ; 29 cm.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

As teorias mais influentes acerca do funcionamento do córtex pré-frontal (PFC) tomam essa estrutura como um córtex de associação e de integração de informações oriundas de outras estruturas nervosas. Isso implicaria na participação direta do PFC nos processos de memória operacional e em processo atencionais. Estudos hodológicos e neurofisiológicos sugerem, que o córtex orbitofrontal (OFC) seria responsável pela integração de informações de caráter sensorial, motivacional e afetivo, enquanto o córtex pré-frontal ventromedial (vmPFC) seria diretamente ligado ao OFC, tendo um papel crucial na codificação de estímulos emocionais oriundos da amígdala. Nesse contexto, é aceito que a integração das informações feita por essas estruturas seja essencial para o processo de tomada de decisões, uma vez que esse comportamento necessita de uma avaliação do ambiente em termos de comparações de situações novas a experiências prévias armazenadas na memória, assim como um balanço entre custos, benefícios e cálculo de possíveis valores da recompensa. Para testar essas hipóteses, ratos com danos seletivos no vmPFC foram submetidos testes de avaliação de ansiedade e medo condicionado no paradigma de teste e reteste no labirinto em cruz elevado (LCE), assim como a testes de memória de referência espacial e memória operacional no labirinto aquático de Morris. Outro grupo de animais teve matrizes de multi-eletrodos implantadas no OFC para a avaliação da atividade neuronal dessa estrutura em um teste envolvendo tomada de decisões, no qual devem escolher entre ganhar 1 pellet de chocolate imediatamente ou 4 pellets envolvendo atrasos variados. No teste no LCE, animais com lesão no vmPFC diferem dos animais controle por apresentarem uma diminuição do tempo de avaliação de risco sem apresentar alterações nos parâmetros que aferem memória, atividade locomotora e ansiedade. No teste de memória de referência espacial após treinamento extensivo de busca pela plataforma em um mesmo local no labirinto aquático, animais com lesão persistem no local quando se retira a plataforma (probe test). Já no teste de memória operacional, no qual a localização da plataforma é alterada diariamente, esses animais não diferem do grupo controle. Na tarefa envolvendo tomada de decisões, observou-se uma atividade eletrofisiológica de neurônios do OFC relacionada ao momento crítico no qual o animal deve realizar uma escolha. Em conjunto, esses resultados mostram que o vmPFC está relacionado à flexibilidade comportamental e tomada de decisões, possivelmente em conjunto com o OFC, cuja atividade neuronal sugere uma participação nos processos de tomada de decisões e de elaboração de estratégias / The most influential theories on the function of the prefrontal cortex (PFC) suggest that this structure is an association cortex, responsible for integration of information received from other parts of the brain. This would implicate in direct participation of the PFC in working memory and attentional processes. Given this context, hodological and neurophysiological studies suggest that the orbitofrontal cortex (OFC) would be responsible for the integration of sensory, motivational and affective aspects, while the ventromedial prefrontal cortex (vmPFC), which is directly connected to the OFC, would have a key role in encoding emotional stimuli from the amygdala. It is well accepted that the processing of these aspects of information is crucial for decision-making processes, given the fact that this expression of behavior requires an evaluation of the environment in terms of comparing novel situation to previous experiences, as well as processing the balance between costs, outcomes and reward values. In order to test these hypotheses, rats with selective lesions to the vmPFC were subjected to the elevated plus maze (EPM) to evaluate anxiety and conditioned fear in the test retest paradigm. Animal were also tested in a spatial reference memory and a working memory tasks in the Morris water maze. Another group of rats had multi-electrode arrays chronically implanted in the OFC for the evaluation of the neuronal activity during a decision-making task, in which the animals had to choose between a small reward of one chocolate pellet immediately and a large reward of four chocolate pellets after varying delays. The results of the EPM show that animals with lesion to the vmPFC differ from control animals by showing diminished time evaluating risk in the second exposure to the EPM, without damage to locomotor activity, memory and anxiety levels. In the reference spatial memory task in the water maze, after extensive training searching for the hidden platform in the same location, lesioned animals persisted searching for the platform in that particular location after it was removed (probe test). However, in the working memory task, in which the platform is presented in a different location each day, lesioned animals did not differ from control animals. In the decision-making task, differential electrophysiological activity in OFC neurons was observed, particularly in the moment of the task in which the animal was required to perform the choice between rewards. Together, these results suggest that the vmPFC is related to behavioral flexibility and decision-making, possibly acting together with the OFC, which neuronal activity suggests participation in decision-making processes

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder that affects roughly 1 in 3500 individuals. In addition to physical features (e.g., neurofibromas), developmental disorders are also common that can affect cognition, learning, attention and social function. The NF1 gene encodes neurofibromin, a GTPase activating protein (GAP)-like protein that negatively regulates Ras GTPase activation. Mutation at the NF1 locus increases the output of MAPK and PI3K signal transduction from the cellular membrane to the nucleus. Similar to humans, Nf1+/- mice show spatial learning abnormalities that are potentially correlated with increases in GABA-mediated inhibition and deficits in long-term potentiation in the hippocampus. Here, we demonstrate for the first time that Nf1+/- mice exhibit a selective loss of long-term social learning / memory and increased GABAergic inhibition in the basolateral amygdala, a critical brain region for regulating social behaviors. Next, utilizing a genetic intercross, we show that the co-deletion of p21-activated kinase type 1 (Pak1-/-), which positively regulates MAPK activation, restores Nf1+/--dependent MAPK hyperactivation in neurons cultured from the frontal cortex. We found that the co-deletion of Pak1 in Nf1+/- mice (Nf1+/- / Pak1-/-) also restores the deficits in long-term social learning / memory seen in Nf1+/- mice and normalizes the increases in GABA-mediated inhibition in the BLA, as compared to Nf1+/- mice. Together, these findings establish a role for Nf1 and Pak1 genes in the regulation of social learning in Nf1-deficient mice. Furthermore, proteomic studies identify dysregulation of F-actin and microtubule dynamics in the prefrontal cortex, and implicate proteins associated with vesicular release as well as neurite formation and outgrowth (e.g., LSAMP, STXBP1, DREB). In the BLA, disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) was identified, and ADAM22 may play a role in the regulation of AMPA receptors. Finally, due to the increased co-occurrence of NF1 and autism, these findings may also have important implications for the pathology and treatment of NF1-related social deficits and some forms of autism.

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