No description available.

Exercise is emerging as a promising low-cost intervention to mitigate age-related memory decline and promote successful aging. Aerobic exercise training enhances cardiorespiratory fitness (CRF) and improves integrity of the medial temporal lobe (MTL) memory system. The hippocampus, a brain region located within the MTL, is critically involved in episodic and spatial memory formation, including spatial navigation, and demonstrates subfield-specific plasticity in response to aerobic exercise among both animals and young adult humans. Yet it remains unclear whether hippocampal subfield-specific exercise training and CRF effects also extend to older adults. Another modulator of structural and functional integrity of the MTL is chronic stress. Importantly, chronic stress was shown to predominantly impact brain regions such as the hippocampus and associated cognitive functions, including episodic memory, that are highly vulnerable to the effects of chronic stress and decline with age. Allostatic load (AL), or the integrative biological dysregulation of multiple biological systems resulting from chronic stress, is associated with poorer cognition, and reduced structural brain integrity. Black Americans were shown to have high burden of AL compared to non-Hispanic White Americans, and this was associated with reports of greater perceived discrimination, a salient psychosocial stressor, among the former group. Although race is a sociocultural construct, Black-White disparities exist in cognitive task performance, and risk of Alzheimer’s disease (AD) and dementia, with Black Americans displaying significantly worse cognitive task performance scores, and a greater likelihood to be diagnosed with AD and dementia compared to non-Hispanic White Americans. Thus, greater AL and discriminatory experiences in Black compared to non-Hispanic White older adults may underlie the racial disparity in neurocognitive aging. The goal of this dissertation was to examine the opposing impact of chronic stress and exercise on neurocognitive aging. This was accomplished by 1) investigating aerobic exercise intervention effects on hippocampal subfield volume and fMRI activity during spatial navigation, a complex cognitive function that declines with age and that is, in part, supported by the MTL (Project 1), 2) examining the effect of AL as a cumulative, physiological stress measure on neurocognitive aging (Project 2), and 3) examining the effect of chronic psychosocial stress through the lens of social discrimination on the functional connectivity of the MTL subsystem of the default mode network, a resting state network that has been linked to episodic memory (Project 3). The secondary aim of this dissertation was to look at the effect of AL (Project 2) and social discrimination (Project 3) on racial neurocognitive disparities in cognitively intact older Black and non-Hispanic White adults. In the first project, data from two randomized controlled clinical trials of aerobic exercise intervention targeting healthy, initially sedentary adults aged 55-85 years were used to examine the effect of exercise training and exercise-related CRF on the hippocampal integrity on the subfield level. Both randomized controlled trials randomly assigned participants to either: aerobic exercise group or active control group and underwent baseline and end-of-study fitness testing, cognitive testing, and high resolution structural and functional MRI. The first objective of this project aimed to test whether aerobic exercise training increases CRF level, which, in turn, increases anterior hippocampal subfield volume and/or attenuates volumetric decline among older adults undergoing aerobic exercise training compared to those in the active control group. Partially supporting our prediction, results displayed that following the period of the 12-week exercise intervention, the active control group but not the aerobic exercise group showed a right dentate gyrus (DG) head volumetric decline that was trending toward statistical significance. Additionally, a positive significant association between changes in CRF and left subiculum (SUB) head volume following the exercise intervention among women was found. The second objective sought to examine whether aerobic exercise intervention modulates the activation in the hippocampus in a subfield-specific manner during virtual reality navigation task performance, particularly modulating activation in the SUB subfield. Consistent with our structural results an increase in CRF was associated with a decrease fMRI activity in the left SUB. Whole-brain analysis during virtual reality navigation task performance showed that an increase in CRF was associated with a decrease in fMRI activity in the cuneus and right middle frontal gyrus, both brain regions that repeatedly display activation during virtual navigation. In the second project, existing data from the Framingham Heart Study (FHS) was used. Cognitively intact men and women, who identified as either Black or African American from the first multiracial Omni group 1 cohort (OMNI1), or White non-Hispanic from the second-generation cohort (Gen2), and were native English speakers, were included in the study. AL was calculated using the values for 10 biomarkers available in the FHS database for the two cohorts studied that are biomarkers for immune, metabolic, and cardiovascular system function. The objective of this project sought to test the prediction that AL correlates with cognitive function and brain structures, particularly hippocampal volume. We additionally sought to examine the secondary prediction that AL mediates the relationship between race and cognitive task performance and structural brain integrity, in age- sex- and education matched racial groups of cognitively intact older adults after controlling for quality of education, cardiovascular-related comorbidities and depression in the FHS cohorts. Results demonstrated that there was no significant correlation between AL and cognitive and brain volumetric measures, however there were significant Black-White disparities in cognitive task performance in verbal and visual learning and memory, abstract reasoning and attention span. These Black-White cognitive task performance disparities existed even after controlling for quality of education, and cardiovascular-related comorbidities. Although there was no significant racial disparity in the mean score of AL index, our physiological stress measure, AL partially explained the observed Black-White disparity in cognitive task performance in verbal learning and memory. Importantly the observed AL effect was not driven by the cardio-metabolic component biomarkers that are part of the AL index, known to overlap with cardiovascular risk factors, but rather, the AL index drove this effect as a whole. There were no racial disparities in brain volumetric measures after controlling for cardiovascular-related comorbidities. Furthermore, there were no sex differences in the effect of AL in any of our neurocognitive outcome measures. In the third project, cognitively intact older Black and White adults (aged 55-80 years) were recruited from the greater Boston area. To measure perceived social discrimination, participants were asked to complete the Experiences of Discrimination questionnaires. Additionally, participants underwent fMRI scanning to examine the functional connectivity of resting-state brain networks. This project sought to test the prediction that greater perceived everyday discrimination would be associated with alteration of resting state functional connectivity, particularly in the MTL subsystem. Results showed that greater perceived everyday discrimination predicted stronger resting-state connectivity between the MTL subsystem, and a cluster located in the right control network, suggesting that perceived discrimination, a psychosocial stressor, may cause functional alteration in brain networks supporting memory and cognitive control in older adults. In conclusion, findings of these studies suggest a neuroprotective effect of exercise, where exercise may attenuate aging-related decline in the structure and function of hippocampal subfields, especially among women, and possibly by targeting the SUB. Furthermore, findings of these studies suggest stress related mechanisms underlying neurocognitive integrity, particularly in the MTL memory system.

No description available.

Thesis (M.Sc.). / Written for the Dept. of Neurology and Neurosurgery. Title from title page of PDF (viewed 2008/12/07). Includes bibliographical references.

Thesis (doctoral)--Westfälischen Wilhelms-Universität zu Münster, 1995. / Includes bibliographical references.

Theoretical models of information storage in the brain have suggested that neurons may undergo an experience-dependent tuning or sharpening of their representations in order to maximize the amount of information that can be stored. Changes in the tuning profiles of neurons have been demonstrated to occur when animals must learn perceptual discriminations, however, whether similar changes occur in the absence of behavioral demands is unclear. To address these questions, the activity of simultaneously recorded medial temporal lobe (MTL) neurons was studied in relation to a passive visual recognition memory task. The structure of this task was such that it allowed for a comparison between novelty related responses as well as tuning properties of individual neurons. A total of 565 well isolated single neurons were recorded. The first contribution of this dissertation is the finding of a dissociation between different medial temporal lobe regions such that neurons in temporal area F (TF), but not perirhinal cortex (PRC) or the hippocampus, show an experience-dependent change in their stimulus selectivity. This finding indicates that tuning of stimulus representations may be an effective mechanism for maximizing information storage in some brain regions. The absence of stimulus tuning in higher level association regions (i.e. TF and PRC) suggests that tuning in these regions may be disadvantageous due to the need to construct unified representations across sensory modalities. A complimentary question to the question of network storage capacity is how networks avoid saturation in the connections between neurons. The second contribution of this dissertation is the finding that there exists a decrease in the magnitude of the short time scale correlations between pairs of neurons; suggesting that networks reduce the number of connections between neurons as a stimulus becomes familiar. Gamma oscillations have been proposed to be the mechanism by which groups of neurons coordinate their activity. However, network coordination has only been indirectly measured. The final contribution of this dissertation is the finding that the magnitude of gamma oscillations is strongly correlated with enhanced magnitude of correlations between neurons.

It is well established that patients with temporal lobe epilepsy (TLE) commonly report memory difficulties. The aim of this thesis was to use a novel approach adopting Nelson & Narens' (1990) theoretical framework to investigate whether metacognitive knowledge and memory performance were differentially disrupted in patients with TLE. More specifically, investigating to what extent poor memory in TLE could result from inadequate metamemory monitoring, inadequate metamemory control or both. Experiment I employed a combined Judgement-of-Learning and Feeling-of-Knowing task to investigate whether participants could monitor their memory successfully at both the item-by-item and global levels. The results revealed a dissociation between memory and metamemory in TLE patients. TLE patients presented with a clear episodic memory deficit compared with controls yet preserved metamemory abilities. Experiments 2 and 3 explored the sensitivity approach to examine metacognitive processes that operate during encoding in TLE patients and controls. Both these experiments demonstrated that TLE patients were sensitive to monitoring and control processes at encoding. The final experiment further investigated memory performance by examining the role of lateralisation of the seizure focus using material specific information and the 'Remember-Know' paradigm. The findings from the verbal task provided partial support to the material-specific hypothesis. The results from these experiments are discussed in terms of their association with executive functioning and memory deficits in TLE, and have important implications for future research examining memory and metamemory in TLE patients and other clinical populations.

<p>Temporal lobe epilepsy is a common and devastating disorder that features recurrent seizures and is often associated with pathologic anxiety and hippocampal sclerosis. An episode of prolonged seizures (status epilepticus) is thought to promote development of human temporal lobe epilepsy years later. A chemical-genetic approach established proof of concept that transiently inhibiting the receptor tyrosine kinase, TrkB, following status epilepticus prevented epilepsy, anxiety-like behavior and hippocampal damage in a mouse model, providing rationale for developing a therapeutic targeting TrkB signaling. To circumvent the undesirable consequence that global inhibition of TrkB exacerbates neuronal degeneration following status epilepticus, we sought to identify both the TrkB-activated signaling pathway mediating these pathologies and a compound that uncouples TrkB from the responsible signaling effector. To accomplish these goals, we used genetically modified mice and a model of seizures and epilepsy induced by a chemoconvulsant. Genetic inhibition of TrkB-mediated phospholipase C gamma 1 (PLC gamma 1) signaling suppressed seizures induced by a chemoconvulsant, leading to design of a peptide (pY816) that inhibited the interaction of TrkB with PLC gamma 1. We demonstrate that pY816 selectively inhibits TrkB-mediated activation of PLC gamma 1 both in vitro and in vivo. Treatment with pY816 prior to administration of a chemoconvulsant suppressed seizures in a dose- and time-dependent manner. Treatment with pY816 initiated after chemoconvulsant-evoked status epilepticus and continued for just three days suppressed seizure-induction of epilepsy, anxiety-like behavior and hippocampal damage assessed months later. This study elucidates the signaling pathway by which TrkB activation produces diverse neuronal activity-driven pathologies and demonstrates therapeutic benefits of an inhibitor of this pathway in an animal model in vivo. A strategy of uncoupling a receptor tyrosine kinase from a signaling effector may prove useful in diverse diseases in which excessive receptor tyrosine kinase signaling contributes.</p> / Dissertation

Introdução: A epilepsia é uma doença de grande relevância médica e social, trazendo grande impacto aos pacientes e a sociedade como um todo. A Epilepsia do Lobo Temporal Mesial (ELTM) é a epilepsia refratária mais prevalente, tendo em sua causalidade o impacto do desequilíbrio entre circuitos neuronais excitatórios e inibitórios, necessitando da remoção cirúrgica das estruturas alteradas e da interrupção das suas vias para melhor controle das crises e qualidade de vida dos pacientes. Objetivo: Buscando ampliar o esclarecimento do papel da amígdala junto as modificações intrínsecas nos receptores de neurotransmissores e em suas subunidades nos mecanismos de ictogênese e epileptogênese, possibilitando o aprimoramento das técnicas cirúrgicas atualmente empregadas, além de novas modalidades terapêuticas, o presente estudo analisou as expressões gênicas das subunidades de receptores excitatórios, NMDA (NR2C e NR3A, genes GRIN2C e GRIN3A), Cainato (GluK1 e GluK2, genes GRIK1 e GRIK2), e subunidade de receptor inibitório GABAA (?4 e ?5, genes GABRA4 e GABRA5) e subtipos de receptor de neuropeptídio Y (Y2 e Y5, com genes NPY2R e NPY5R), em núcleos basolaterais de amígdalas humanas de pacientes com ELTM. Material e Métodos: Foram utilizados fragmentos de amígdala de 20 pacientes que fizeram amigdalohipocampectomia junto ao Serviço de Neurocirurgia do HC-FMRP-USP, sendo 10 pacientes com controle efetivo pós-operatório (Engel 1) e 10 pacientes com controle inadequado das crises(Engel 3 e 4), 10 amígdalas obtidas de autópsias (controle), utilizando a qPCR. Resultados: Foram evidenciadas diferenças da expressão nas subunidades NR2C (p=0,006) e ?4 do GABAAr (p=0,008), subtipo de NPYr Y2(p=0.013), com tendência junto a subunidade NR3A(p=0,077). Não evidenciando significância estatísticas nas análises das subunidades GluK1(p=0,147), GluK2(p=0,182) e?5 do GABAAr (p=0,272), para o subtipo NPYr Y1(p=0,242). Conclusão: As análises sugerem diferenças na expressão de receptores de neurotransmissores em pacientes com epilepsia em relação ao controle contendo as subunidadeNR2C e ?4 do GABAAr, com tendências a subunidade NR3A, indicando modificações neuronais amigdalianas possivelmente envolvidas com a zona epileptogênica, possibilitando aprimoramentos terapêuticos junto ao tratamento dasepilepsias refratárias. Também podemos inferir que os mecanismos neuronais envolvendo as subunidades?4 doGABAAr e GRIN2C, e do subtipo Y2 do NPYr na epileptogênese e ictogênese da ELTM podem ser semelhantes entre amígdala e hipocampo, enquanto os envolvendo as subunidades GLUK1 e GLUK2 parecem ser diferenciados; o gene GABRA5 pode ser utilizado como gene de controle endógeno em estudos com amigdala e hipocampo na ELTM. / Introduction: Epilepsy is a disease whith highly medical and social relevance, bringing impact on patients and society as a whole. Mesial Temporal Lobe Epilepsy (MTLE) is the most prevalent refractory epilepsy, in its causality the impact of the imbalance between excitatory neuronal circuits and inhibitory, needing a surgical removal of the altered structures and the interruption of their way to better seizure control and quality of life pacientes. Goal: Searching to increase understanding the role of the amygdala with intrinsic changes in neurotransmitter receptors and their subunits in ictogenesis mechanisms and epileptogenesis, enabling the improvement of surgical techniques currently used, as well as new therapeutic modalities, this study analyzed gene expression on the subunits of excitatory receptors, NMDA (NR2 and NR3A, GRIN2C and GRIN3A genes) and kainate (GluK1 and GluK2, GRIK1 and GRIK2 genes), and inhibitory receptor subunit GABA (?4 and ?5, genes GABRA4 and GABRA5 ), neuropeptide Y receptor subtypes (Y2 and Y5, and NPY5R with NPY2R gene) in the basolateral nucleus of human amygdala of patients with MTLE. Material and Methods: Amygdala fragments were used in 20 patients who made amigdalohipocampectomia with the Service neurosurgery HC-FMRP-USP, 10 patients with postoperative effective control (Engel 1) and 10 patients with inadequate control of seizures (Engel 3:04), and 10 amygdalas obtained from autopsies (control) using qPCR. Results: Were differences evidenced expression in NR2C subunits (p = 0.006) e?4 the GABAAr (p = 0.008), and subtype NPYr Y2 (p = 0.013), along with a tendency of NR3A subunits (p = 0.077). Showing no statistical significance in the analysis of GluK1 subunits (p = 0.147), GluK2 (p = 0.182) e?5 the GABAAr (p = 0.272), and the NPYr Y1 subtype (p = 0.242). Conclusion: The analyzes suggest differences in expression of neurotransmitter receptors in epilepsy patients on control containing the NR2C subunits and ?4 of GABAAr with NR3A subunits trends indicating amygdala neuronal modifications possibly involved in the epileptogenic zone, enabling therapeutic improvements with the refractory epilepsy treatment. As well can infer that the neural mechanisms involving the subunits ?4 GABAAr, GRIN2C and Y2 NPYr subtype in epileptogenesis and ictogenesis of TLE can be similar between the amygdala and hippocampus, while involving GLUK1 and GLUK2 subunits appear to be different; the GABRA5 gene can be used as endogenous control gene in studies of hippocampus and amygdala in TLE.

Introdução: A epilepsia é uma doença de grande relevância médica e social, trazendo grande impacto aos pacientes e a sociedade como um todo. A Epilepsia do Lobo Temporal Mesial (ELTM) é a epilepsia refratária mais prevalente, tendo em sua causalidade o impacto do desequilíbrio entre circuitos neuronais excitatórios e inibitórios, necessitando da remoção cirúrgica das estruturas alteradas e da interrupção das suas vias para melhor controle das crises e qualidade de vida dos pacientes. Objetivo: Buscando ampliar o esclarecimento do papel da amígdala junto as modificações intrínsecas nos receptores de neurotransmissores e em suas subunidades nos mecanismos de ictogênese e epileptogênese, possibilitando o aprimoramento das técnicas cirúrgicas atualmente empregadas, além de novas modalidades terapêuticas, o presente estudo analisou as expressões gênicas das subunidades de receptores excitatórios, NMDA (NR2C e NR3A, genes GRIN2C e GRIN3A), Cainato (GluK1 e GluK2, genes GRIK1 e GRIK2), e subunidade de receptor inibitório GABAA (?4 e ?5, genes GABRA4 e GABRA5) e subtipos de receptor de neuropeptídio Y (Y2 e Y5, com genes NPY2R e NPY5R), em núcleos basolaterais de amígdalas humanas de pacientes com ELTM. Material e Métodos: Foram utilizados fragmentos de amígdala de 20 pacientes que fizeram amigdalohipocampectomia junto ao Serviço de Neurocirurgia do HC-FMRP-USP, sendo 10 pacientes com controle efetivo pós-operatório (Engel 1) e 10 pacientes com controle inadequado das crises(Engel 3 e 4), 10 amígdalas obtidas de autópsias (controle), utilizando a qPCR. Resultados: Foram evidenciadas diferenças da expressão nas subunidades NR2C (p=0,006) e ?4 do GABAAr (p=0,008), subtipo de NPYr Y2(p=0.013), com tendência junto a subunidade NR3A(p=0,077). Não evidenciando significância estatísticas nas análises das subunidades GluK1(p=0,147), GluK2(p=0,182) e?5 do GABAAr (p=0,272), para o subtipo NPYr Y1(p=0,242). Conclusão: As análises sugerem diferenças na expressão de receptores de neurotransmissores em pacientes com epilepsia em relação ao controle contendo as subunidadeNR2C e ?4 do GABAAr, com tendências a subunidade NR3A, indicando modificações neuronais amigdalianas possivelmente envolvidas com a zona epileptogênica, possibilitando aprimoramentos terapêuticos junto ao tratamento dasepilepsias refratárias. Também podemos inferir que os mecanismos neuronais envolvendo as subunidades?4 doGABAAr e GRIN2C, e do subtipo Y2 do NPYr na epileptogênese e ictogênese da ELTM podem ser semelhantes entre amígdala e hipocampo, enquanto os envolvendo as subunidades GLUK1 e GLUK2 parecem ser diferenciados; o gene GABRA5 pode ser utilizado como gene de controle endógeno em estudos com amigdala e hipocampo na ELTM. / Introduction: Epilepsy is a disease whith highly medical and social relevance, bringing impact on patients and society as a whole. Mesial Temporal Lobe Epilepsy (MTLE) is the most prevalent refractory epilepsy, in its causality the impact of the imbalance between excitatory neuronal circuits and inhibitory, needing a surgical removal of the altered structures and the interruption of their way to better seizure control and quality of life pacientes. Goal: Searching to increase understanding the role of the amygdala with intrinsic changes in neurotransmitter receptors and their subunits in ictogenesis mechanisms and epileptogenesis, enabling the improvement of surgical techniques currently used, as well as new therapeutic modalities, this study analyzed gene expression on the subunits of excitatory receptors, NMDA (NR2 and NR3A, GRIN2C and GRIN3A genes) and kainate (GluK1 and GluK2, GRIK1 and GRIK2 genes), and inhibitory receptor subunit GABA (?4 and ?5, genes GABRA4 and GABRA5 ), neuropeptide Y receptor subtypes (Y2 and Y5, and NPY5R with NPY2R gene) in the basolateral nucleus of human amygdala of patients with MTLE. Material and Methods: Amygdala fragments were used in 20 patients who made amigdalohipocampectomia with the Service neurosurgery HC-FMRP-USP, 10 patients with postoperative effective control (Engel 1) and 10 patients with inadequate control of seizures (Engel 3:04), and 10 amygdalas obtained from autopsies (control) using qPCR. Results: Were differences evidenced expression in NR2C subunits (p = 0.006) e?4 the GABAAr (p = 0.008), and subtype NPYr Y2 (p = 0.013), along with a tendency of NR3A subunits (p = 0.077). Showing no statistical significance in the analysis of GluK1 subunits (p = 0.147), GluK2 (p = 0.182) e?5 the GABAAr (p = 0.272), and the NPYr Y1 subtype (p = 0.242). Conclusion: The analyzes suggest differences in expression of neurotransmitter receptors in epilepsy patients on control containing the NR2C subunits and ?4 of GABAAr with NR3A subunits trends indicating amygdala neuronal modifications possibly involved in the epileptogenic zone, enabling therapeutic improvements with the refractory epilepsy treatment. As well can infer that the neural mechanisms involving the subunits ?4 GABAAr, GRIN2C and Y2 NPYr subtype in epileptogenesis and ictogenesis of TLE can be similar between the amygdala and hippocampus, while involving GLUK1 and GLUK2 subunits appear to be different; the GABRA5 gene can be used as endogenous control gene in studies of hippocampus and amygdala in TLE.