Project description:Human MRI studies show that experience can lead to changes in the volume of task-specific brain regions; however, the behavioural and molecular processes driving these changes remain poorly understood. Here, we used in-vivo mouse MRI and RNA sequencing to investigate the neuroanatomical and transcriptional changes induced by environmental enrichment, exercise, and social interaction. Additionally, we asked whether the volume changes require CREB, a transcription factor critical for memory formation and neuronal plasticity. Enrichment rapidly increased cortical and hippocampal volume, and these effects were not attributable to exercise or social interaction. Instead, they likely arise from learning and sensorimotor experience. Nevertheless, the volume changes were not attenuated in mice with memory impairments caused by loss of CREB, indicating that these effects are driven by processes distinct from this canonical learning and memory pathway. Finally, within brain regions that underwent volume changes, enrichment increased the expression of genes associated with axonogenesis, dendritic spine development, synapse structural plasticity, and neurogenesis, suggesting these processes underlie the volume changes detected with MRI.
Project description:The functional output of the hippocampus, a brain region subserving memory processes, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. The structural requirements of such plasticity and molecular processes involved in this regulation are poorly understood. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in serving a pro-plasticity role in the hippocampus, a role that decreases with brain aging. Here, we report that TIMP2 is highly expressed by neurons within the hippocampus and its loss drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory. We find that TIMP2 regulates accumulation of extracellular matrix (ECM) around synapses in the hippocampus with concomitant hindrance in migration of newborn neurons through a denser ECM network. A conditional TIMP2 KO mouse reveals that neuronal TIMP2 regulates adult neurogenesis, accumulation of ECM, and ultimately hippocampus-dependent memory. Our results define a mechanism whereby hippocampus-dependent function is regulated by TIMP2 and its interactions with the ECM to regulate diverse processes associated with synaptic plasticity.
Project description:We used an in vitro pool based strategy to probe the sequence and structural requirements for mRNA target recognition by the yeast tRNA pseudouridine synthase Pus1.
Project description:The phenotype of an organism results from its genotype and the influence of the environment throughout development. Even when using animals of the same genotype, independent studies may test animals of different phenotypes, resulting in poor replicability due to genotype-by-environment interactions. Thus, genetically defined strains of mice may respond differently to experimental treatments depending on their rearing environment. However, the extent of such phenotypic plasticity and its implications for the replicability of research findings have remained unknown. Here, we examined the extent to which common environmental differences between animal facilities modulate the phenotype of genetically homogeneous (inbred) mice. We conducted a comprehensive multi-center study, whereby inbred C57BL/6J mice from a single breeding cohort were allocated to and reared in five different animal facilities throughout early life and adolescence, before being transported to a single test laboratory. We found persistent effects of the rearing facility on the composition and heterogeneity of the gut microbial community. These effects were paralleled by persistent differences in body weight and in the behavioural phenotype of the mice. Furthermore, we show that environmental variation among animal facilities is strong enough to influence epigenetic patterns in neurons at the level of chromatin organization. We detected changes in chromatin organization in the regulatory regions of genes involved in nucleosome assembly, neuronal differentiation, synaptic plasticity and regulation of behaviour. Our findings demonstrate that common environmental differences between animal facilities may produce facility-specific phenotypes, from the molecular to the behavioural level. Furthermore, they highlight an important limitation of inferences from single-laboratory studies and thus argue that study designs should take environmental background into account to increase the robustness and replicability of findings.
Project description:Experience-dependent synaptic plasticity refines brain circuits during development. To uncover protein synthesis-dependent mechanisms contributing to experience-dependent plasticity, we performed quantitative proteomic analysis of the nascent proteome using improved bio-orthogonal metabolic labeling (BONCAT) to identify candidate plasticity proteins (CPPs) that undergo differential protein synthesis in response to visual conditioning (VC) in Xenopus optic tectum. We identified 83 CPPs that formed strongly connected networks and were annotated to a variety of biological functions, including RNA splicing, protein translation, and chromatin remodeling. Functional analysis of select CPPs using translation blocking morpholinos revealed the requirement of eukaryotic initiation factor 3 subunit A (eIF3A), fused in sarcoma (FUS), and ribosomal protein s17 (RPS17) in experience-dependent structural plasticity of tectal neurons. These results demonstrate that the nascent proteome is dynamic in response to VC and that de novo synthesis of the machinery that regulates gene expression and protein translation is required for experience-dependent structural plasticity.
Project description:Structural genetic variants like copy number variants (CNVs) comprise a large part of human genetic variation and may be inherited as well as somatically acquired. Recent studies have reported the presence of somatically acquired structural variants in the human genome and it has been suggested that they may accumulate in elderly individuals. To further explore the presence and the age-related acquisition of somatic structural variants in the human genome, we investigated CNVs acquired over a period of 10 years in 86 elderly Danish twins as well as CNV discordances between co-twins of 18 monozygotic twin pairs. Furthermore, the presence of mosaic structural variants was explored.