Neuroscience
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Alpha-synuclein (a-syn) is the major component of the intracytoplasmic inclusions known as Lewy bodies (LB), which constitute the hallmark of Parkinson's disease (PD). Mice overexpressing human a-syn under the Thy-1 promoter (ASO) show slow neurodegeneration and some behavioral deficits similar to those seen in human PD patients. Here, we describe a whole-brain distribution of human a-syn in adult ASO mice. ⋯ This immunohistochemical study provides an anatomical map of the human a-syn distribution in ASO mice. Our data show that human a-syn, although not present at levels that were detectable by immunostaining in dopaminergic neurons of substantia nigra or noradrenergic neurons of locus coeruleus, was highly expressed in other PD relevant regions of the brain in different neuronal subtypes. These data will help to relate a-syn expression to the phenotypic manifestations observed in this widely used mouse line.
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The ability to discriminate between closely related contexts is a specific form of hippocampal-dependent learning that may be impaired in certain neurodegenerative disorders such as Alzheimer's and Down Syndrome. However, signaling pathways regulating this form of learning are poorly understood. Previous studies have shown that the calcium-dependent exchange factor Ras-GRF1, an activator of Rac, Ras and R-Ras GTPases, is important for this form of learning and memory. ⋯ Like the loss of GRF1, knockdown of R-Ras in the CA1 also impairs the induction of HFS-LTP and p38 Map kinase. Nevertheless, experiments indicate that this involvement of R-Ras in HFS-LTP that is required for contextual discrimination is independent of Ras-GRF1. Thus, R-Ras is a novel regulator of a form of hippocampal-dependent LTP as well as learning and memory that is affected in certain forms of neurodegenerative diseases.
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Conduction time is typically ignored in computational models of neural network function. Here we consider the effects of conduction delays on the synchrony of neuronal activity and neural oscillators, and evaluate the consequences of allowing conduction velocity (CV) to be regulated adaptively. We propose that CV variation, mediated by myelin, could provide an important mechanism of activity-dependent nervous system plasticity. ⋯ Myelin plasticity, as another form of activity-dependent plasticity, is relevant not only to nervous system development but also to complex information processing tasks that involve coupling and synchrony among different brain rhythms. We use coupled oscillator models with time delays to explore the importance of adaptive time delays and adaptive synaptic strengths. The impairment of activity-dependent myelination and the loss of adaptive time delays may contribute to disorders where hyper- and hypo-synchrony of neuronal firing leads to dysfunction (e.g., dyslexia, schizophrenia, epilepsy).
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Since its introduction in the early 1990s, diffusion-weighted magnetic resonance imaging (MRI) has played a crucial role in the non-invasive evaluation of tissue microstructure of brain parenchyma in vivo. Diffusion anisotropy, in particular, has been extensively used to infer histological changes due to brain maturation and pathology, as it shows a clear dependence on tissue architecture. Although the resolution used in most studies lies in the macroscopic range, the information provided originates at the microscopic level and, as such, diffusion MRI serves as a microscope that can reveal profound details of tissue with direct clinical and research applications. ⋯ Animal models may provide insight into the mechanisms involved, but do not necessarily provide accurate representations of the human condition, making human diffusion MRI studies with direct histological confirmation crucial for our understanding of tissue changes secondary to neurodevelopment and disease. This work provides a synopsis of tissue characteristics that give rise to highly informative, specific diffusion patterns, and also of how methodological and artifactual aspects can provide erroneous diffusion measurements that do not accurately reflect tissue and may lead to misinterpretation of results. Examples of diffusion changes due to human conditions are provided to illustrate the wealth of applications of diffusion MRI in clinical and research fields.
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Review
Disconnected aging: cerebral white matter integrity and age-related differences in cognition.
Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. ⋯ We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging.