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Nature Apr 2022There is strong evidence of brain-related abnormalities in COVID-19. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder...
There is strong evidence of brain-related abnormalities in COVID-19. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51-81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans-with 141 days on average separating their diagnosis and the second scan-as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.
Topics: Aged; Aged, 80 and over; Biological Specimen Banks; Brain; COVID-19; Humans; Magnetic Resonance Imaging; Middle Aged; SARS-CoV-2; Smell; United Kingdom
PubMed: 35255491
DOI: 10.1038/s41586-022-04569-5 -
Nature Oct 2021Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is...
Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data enabled prediction of high-confidence enhancer-gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments. By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum.
Topics: Animals; Atlases as Topic; Brain; Chromatin; Cytosine; DNA Methylation; Datasets as Topic; Dentate Gyrus; Enhancer Elements, Genetic; Epigenome; Epigenomics; Gene Expression Profiling; Hippocampus; Male; Mice; Mice, Inbred C57BL; Models, Biological; Neural Pathways; Neurons; Single-Cell Analysis
PubMed: 34616061
DOI: 10.1038/s41586-020-03182-8 -
EC Psychology and Psychiatry Jun 2023The aim of this study is to provide a comprehensive overview of spatial multiomics analysis, including its definition, processes, applications, significance and relevant...
The aim of this study is to provide a comprehensive overview of spatial multiomics analysis, including its definition, processes, applications, significance and relevant research in psychiatric disorders. To achieve this, a literature search was conducted, focusing on three major spatial omics techniques and their application to three common psychiatric disorders: Alzheimer's disease (AD), schizophrenia, and autism spectrum disorders. Spatial genomics analysis has revealed specific genes associated with neuropsychiatric disorders in certain brain regions. Spatial transcriptomics analysis has identified genes related to AD in areas such as the hippocampus, olfactory bulb, and middle temporal gyrus. It has also provided insight into the response to AD in mouse models. Spatial proteogenomics has identified autism spectrum disorder (ASD)-risk genes in specific cell types, while schizophrenia risk loci have been linked to transcriptional signatures in the human hippocampus. In summary, spatial multiomics analysis offers a powerful approach to understand AD pathology and other psychiatric diseases, integrating multiple data modalities to identify risk genes for these disorders. It is valuable for studying psychiatric disorders with high or low cellular heterogeneity and provides new insights into the brain nucleome to predict disease progression and aid diagnosis and treatment.
PubMed: 37424930
DOI: No ID Found -
Cells Sep 2022In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a... (Review)
Review
In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and cerebellum of eutherian species. The formation of these structures starts during embryogenesis and continues postnatally. In both eutherians and marsupials, neurogenesis continues in the subventricular zone of the lateral ventricle (SVZ) and the dentate gyrus of the hippocampal formation throughout life. The majority of proliferated cells from the SVZ migrate to the olfactory bulb, whereas, in the dentate gyrus, cells reside within this structure after division and differentiation into neurons. A key aim of this review is to evaluate advances in understanding developmental neurogenesis that occurs postnatally in both marsupials and eutherians, with a particular emphasis on the generation of granule cells during the formation of the olfactory bulb, dentate gyrus, and cerebellum. We debate the significance of immature neurons in the piriform cortex of young mammals. We also synthesize the knowledge of adult neurogenesis in the olfactory bulb and the dentate gyrus of marsupials by considering whether adult-born neurons are essential for the functioning of a given area.
Topics: Animals; Dentate Gyrus; Eutheria; Mammals; Marsupialia; Neurogenesis
PubMed: 36078144
DOI: 10.3390/cells11172735 -
Frontiers in Neuroscience 2014Neurogenesis continues well beyond embryonic and early postnatal ages in three areas of the nervous system. The subgranular zone supplies new neurons to the dentate... (Review)
Review
Neurogenesis continues well beyond embryonic and early postnatal ages in three areas of the nervous system. The subgranular zone supplies new neurons to the dentate gyrus of the hippocampus. The subventricular zone supplies new interneurons to the olfactory bulb, and the olfactory neuroepithelia generate new excitatory sensory neurons that send their axons to the olfactory bulb. The latter two areas are of particular interest as they contribute new neurons to both ends of a first-level circuit governing olfactory perception. The vomeronasal organ and the main olfactory epithelium comprise the primary peripheral olfactory epithelia. These anatomically distinct areas share common features, as each exhibits extensive neurogenesis well beyond the juvenile phase of development. Here we will discuss the effect of age on the structural and functional significance of neurogenesis in the vomeronasal and olfactory epithelia, from juvenile to advanced adult ages, in several common model systems. We will next discuss how age affects the regenerative capacity of these neural stem cells in response to injury. Finally, we will consider the integration of newborn neurons into an existing circuit as it is modified by the age of the animal.
PubMed: 25018692
DOI: 10.3389/fnins.2014.00182 -
Biomolecules Feb 2020It is now well established that neurogenesis occurs throughout adulthood in select brain regions, but the functional significance of adult neurogenesis remains unclear.... (Review)
Review
It is now well established that neurogenesis occurs throughout adulthood in select brain regions, but the functional significance of adult neurogenesis remains unclear. There is considerable evidence that steroid hormones modulate various stages of adult neurogenesis, and this review provides a focused summary of the effects of testosterone on adult neurogenesis. Initial evidence came from field studies with birds and wild rodent populations. Subsequent experiments with laboratory rodents have tested the effects of testosterone and its steroid metabolites upon adult neurogenesis, as well as the functional consequences of induced changes in neurogenesis. These experiments have provided clear evidence that testosterone increases adult neurogenesis within the dentate gyrus region of the hippocampus through an androgen-dependent pathway. Most evidence indicates that androgens selectively enhance the survival of newly generated neurons, while having little effect on cell proliferation. Whether this is a result of androgens acting directly on receptors of new neurons remains unclear, and indirect routes involving brain-derived neurotrophic factor (BDNF) and glucocorticoids may be involved. In vitro experiments suggest that testosterone has broad-ranging neuroprotective effects, which will be briefly reviewed. A better understanding of the effects of testosterone upon adult neurogenesis could shed light on neurological diseases that show sex differences.
Topics: Androgens; Animals; Brain; Brain-Derived Neurotrophic Factor; Cell Proliferation; Cell Survival; Dentate Gyrus; Female; Glucocorticoids; Hippocampus; Humans; Male; Neurogenesis; Neurons; Neuroprotective Agents; Olfactory Bulb; Testosterone
PubMed: 32028656
DOI: 10.3390/biom10020225