Project description:The brain is able to change its structure and function in response to environmental stimulations. Several human and animal studies have documented that enhanced stimulations provide individuals with strengthened brain structure and function that allow them to better cope with damage. In this framework, studies based on the exposure of animals to environmental enrichment (EE) have provided indications of the mechanisms involved in such a beneficial action. The cerebellum is a very plastic brain region that responds to every experience with deep structural and functional rearrangement. The present review specifically aims to collect and synthesize the evidence provided by animal models on EE exposure effects on cerebellar structure and function by considering the studies on healthy subjects and on animals exposed to EE both before and after damage involving cerebellar functionality. On the whole, the evidence supports the role of EE in enhancing cerebellar compensation and developing cerebellar reserve. However, since studies addressing this issue are still scarce, large areas of inconsistency and lack of clarity remain. Further studies are required to provide suggestions on possible mechanisms of enhancement of compensatory responses in human patients following cerebellar damage.
Project description:The cerebellum contains most of the neurons in the human brain, and exhibits unique modes of development, malformation, and aging. For example, granule cells-the most abundant neuron type-develop unusually late and exhibit unique nuclear morphology. Here, by developing our high-resolution single-cell 3D genome assay Dip-C into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we were able to resolve the first 3D genome structures of single cerebellar cells, create life-spanning 3D genome atlases for both human and mouse, and jointly measure transcriptome and chromatin accessibility during development. We found that while the transcriptome and chromatin accessibility of human granule cells exhibit a characteristic maturation pattern within the first year of postnatal life, 3D genome architecture gradually remodels throughout life into a non-neuronal state with ultra-long-range intra-chromosomal contacts and specific inter-chromosomal contacts. This 3D genome remodeling is conserved in mice, and robust to heterozygous deletion of chromatin remodeling disease-associated genes (Chd8 or Arid1b). Together these results reveal unexpected and evolutionarily-conserved molecular processes underlying the unique development and aging of the mammalian cerebellum.
Project description:Objective: Increased variability in cognition with age has been argued as an indication of pathological processes. Focusing on early detection of neurodegenerative disorders, we investigated variability in cognition in healthy middle-aged adults. In order to understand possible determinants of this variability, we also investigated associations with cognitive reserve, neuroimaging markers, subjective memory complaints, depressive symptomatology, and gender. Method: Thirty-one 50 ± 2 years old individuals were investigated as target group and deviation was studied in comparison to a reference younger group of 30 individuals 40 ± 2 years old. Comprehensive neuropsychological and structural imaging protocols were collected. Brain regional volumes and cortical thickness were calculated with FreeSurfer, white matter hyperintensities with CASCADE, and mean diffusivity with FSL. Results: Across-individuals variability showed greater dispersion in lexical access, processing speed, executive functions, and memory. Variability in global cognition correlated with, reduced cortical thickness in the right parietal-temporal-occipital association cortex, and increased mean diffusivity in the cingulum bundle and right inferior fronto-occipital fasciculus. A trend was also observed for the correlation between global cognition and hippocampal volume and female gender. All these associations were influenced by cognitive reserve. No correlations were found with subjective memory complaints, white matter hyperintensities and depressive symptomatology. Across-domains and across-tasks variability was greater in several executive components and cognitive processing speed. Conclusion: Variability in cognition during middle-age is associated with neurodegeneration in the parietal-temporal-occipital association cortex and white matter tracts connecting this to the prefrontal dorsolateral cortex and the hippocampus. Moreover, this effect is influenced by cognitive reserve. Studying variability offers valuable information showing that differences do not occur in the same magnitude and direction across individuals, cognitive domains and tasks. These findings may have important implications for early detection of subtle cognitive impairment and clinical interpretation of deviation from normality.
Project description:Delirium is a disorder of acute onset with fluctuating symptoms and is character ized by inattention, disorganized thinking and altered levels of consciousness. The risk for delirium is greatest in individual with dementia, and the incidence of both is increasing worldwide because of the aging of our population. Although s clinical trials have tested interventions f delirium prevention in individuals without dementia, little is known about the m anisms for the prevention of delirium i early-stage Alzheimer's disease (AD). Th purpose of this article is to explore ways o preventing delirium and slowing the ra of cognitive decline in early-stage AD enhancing cognitive reserve. An agenda for future research on interventions to prevent delirium in individuals with early-stage AD is also presented.
Project description:Development of optimal vaccines for influenza is challenging, in part as a result of the high antigenic variability in field strains associated with genetic shift from reassortment and genetic drift from point mutations. Discovery of conserved antigenic sites on the hemagglutinin (HA) protein for neutralizing antibodies suggested the possibility that influenza vaccines could be developed that induce focused antibody responses to the conserved neutralizing determinants, especially the HA stem region. Recent studies have focused on the antigenicity and immunogenicity of such domains, using monoclonal antibodies and candidate-engineered HA stem-based vaccines. Much progress has been made, but we still do not fully understand the biology of the immune response to this unique antigenic region.
Project description:Influenza remains a major human pathogen despite seasonal vaccination. At long last, there is energy and resources to develop influenza vaccines that provide more predictable and durable protection. Vaccines based on inducing antibodies to the conserved stem of the viral hemagglutinin (HA) have emerged as leading candidates for broadening population immunity and ultimately limiting antigenic drift. Here, we discuss the knowns and unknowns of HA-specific B-cell and antibody responses. In particular, we focus on how immunodominance sculpts antibody responses and drives antigenic drift. We propose a number of strategies to overcome immunodominance and improve the breadth and efficacy of antibody responses.
Project description:Huntington disease (HD) is associated with decline in cognition and progressive morphological changes in brain structures. Cognitive reserve may represent a mechanism by which disease-related decline may be delayed or slowed. The current study examined the relationship between cognitive reserve and longitudinal change in cognitive functioning and brain volumes among prodromal (gene expansion-positive) HD individuals. Participants were genetically confirmed individuals with prodromal HD enrolled in the PREDICT-HD study. Cognitive reserve was computed as the composite of performance on a lexical task estimating premorbid intellectual level, occupational status, and years of education. Linear mixed effects regression (LMER) was used to examine longitudinal changes on four cognitive measures and three brain volumes over approximately 6 years. Higher cognitive reserve was significantly associated with a slower rate of change on one cognitive measure (Trail Making Test, Part B) and slower rate of volume loss in two brain structures (caudate, putamen) for those estimated to be closest to motor disease onset. This relationship was not observed among those estimated to be further from motor disease onset. Our findings demonstrate a relationship between cognitive reserve and both a measure of executive functioning and integrity of certain brain structures in prodromal HD individuals.
Project description:Cognitive reserve (CR) explains differential susceptibility of cognitive performance to neuropathology. However, as brain pathologies progress, cognitive decline occurs even in individuals with initially high CR. The interplay between the structural brain health (= level of brain reserve) and CR-related brain networks therefore requires further research. Our sample included 142 individuals aged 60-70 years. National Adult Reading Test intelligence quotient (NART-IQ) was our CR proxy. On an in-scanner Letter Sternberg task, we used ordinal trend (OrT) analysis to extract a task-related brain activation pattern (OrT slope) for each participant that captures increased expression with task load (one, three, and six letters). We assessed whether OrT slope represents a neural mechanism underlying CR by associating it with task performance and NART-IQ. Additionally, we investigated how the following brain reserve measures affect the association between NART-IQ and OrT slope: mean cortical thickness, total gray matter volume, and brain volumes proximal to the areas contained in the OrT patterns. We found that higher OrT slope was associated with better task performance and higher NART-IQ. Further, the brain reserve measures were not directly associated with OrT slope, but they affected the relationship between NART-IQ and OrT slope: NART-IQ was associated with OrT slope only in individuals with high brain reserve. The degree of brain reserve has an impact on how (and perhaps whether) CR can be implemented in brain networks in older individuals.
Project description:Computational models have earned broad acceptance for assessing chemical toxicity during early stages of drug discovery or environmental safety assessment. The majority of publicly available QSAR toxicity models have been developed for datasets including mostly drugs or drug-like compounds. We have evaluated and compared chemical spaces occupied by cosmetics, drugs, and pesticides, and explored whether current computational models of toxicity endpoints can be universally applied to all these chemicals. Our analysis of the chemical space overlap and applicability domain (AD) of models built previously for twenty different toxicity endpoints showed that most of these models afforded high coverage (>90%) for all three classes of compounds analyzed herein. Only T. pyriformis models demonstrated lower coverage for drugs and pesticides (38% and 54%, respectively). These results show that, for the most part, historical QSAR models built with data available for different toxicity endpoints can be used for toxicity assessment of novel chemicals irrespective of the intended commercial use; however, the AD restriction is necessary to assure the expected prediction accuracy. Local models may need to be developed to capture chemicals that appear as outliers with respect to global models.
Project description:Mutations of the myosin Va gene cause the neurological diseases Griscelli syndrome type 1 and Elejalde syndrome in humans and dilute phenotypes in rodents. To understand the pathophysiological mechanisms underlying the neurological disorders in myosin Va diseases, we conducted an integrated analysis at the molecular, cellular, electrophysiological, and behavioral levels using the dilute-neurological (d-n) mouse mutant. These mice manifest an ataxic gait and clonic seizures during postnatal development, but the neurological disorders are ameliorated in adulthood. We found that smooth endoplasmic reticulum (SER) rarely extended into the dendritic spines of Purkinje cells (PCs) of young d-n mice, and there were few, if any, IP(3) receptors. Moreover, long-term depression (LTD) at parallel fiber-PC synapses was abolished, consistent with our previous observations in juvenile lethal dilute mutants. Young d-n mice exhibited severe impairment of cerebellum-dependent motor learning. In contrast, adult d-n mice showed restoration of motor learning and LTD, and these neurological changes were associated with accumulation of SER and IP(3) receptors in some PC spines and the expression of myosin Va proteins in the PCs. RNA interference-mediated repression of myosin Va caused a reduction in the number of IP(3) receptor-positive spines in cultured PCs. These findings indicate that myosin Va function is critical for subsequent processes in localization of SER and IP(3) receptors in PC spines, LTD, and motor learning. Interestingly, d-n mice had defects of motor coordination from young to adult ages, suggesting that the role of myosin Va in PC spines is not sufficient for motor coordination.