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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 -
Handbook of Clinical Neurology 2021Emotions can be defined as states elicited by rewards or punishments, and indeed the neurology of emotional disorders can be understood in terms of this foundation. The... (Review)
Review
Emotions can be defined as states elicited by rewards or punishments, and indeed the neurology of emotional disorders can be understood in terms of this foundation. The orbitofrontal cortex in humans and other primates is a critical area in emotion processing, determining the value of stimuli and whether they are rewarding or nonrewarding. The cortical processing that occurs before the orbitofrontal cortex primarily involves defining the identity of stimuli, i.e., "what" is present and not reward value. There is evidence that this holds true for taste, visual, somatosensory, and olfactory stimuli. The human medial orbitofrontal cortex is important in processing many different types of reward, and the lateral orbitofrontal cortex in processing nonreward and punishment. Humans with damage to the orbitofrontal cortex have an impaired ability to identify facial and voice expressions of emotions, and impaired subjective experience of emotion. They can have an altered personality and be impulsive because they are impaired at processing failures to receive expected rewards and at processing punishments. In humans, the role of the amygdala in the processing of emotions is reduced because of the great evolutionary development of the orbitofrontal cortex: amygdala damage has much less effect on emotion than does orbitofrontal cortex damage. The orbitofrontal cortex projects reward value information to the anterior cingulate cortex, which is involved in learning those actions required to obtain rewards and avoid punishments. The cingulate cortex thus provides an output route for emotional behavior. In depression, the medial orbitofrontal cortex has decreased connectivity and sensitivity to reward, and the lateral orbitofrontal cortex has increased connectivity and sensitivity to nonreward. The orbitofrontal cortex has major projections to the anterior cingulate cortex, including its subcommissural region, and the anterior cingulate cortex is also implicated in depression.
Topics: Animals; Emotions; Gyrus Cinguli; Humans; Learning; Prefrontal Cortex; Reward
PubMed: 34389113
DOI: 10.1016/B978-0-12-822290-4.00002-5 -
Ageing Research Reviews Dec 2023In aging, olfactory deficits have been associated with lower cognition and motor function. Olfactory dysfunction is also one of the earliest features of... (Review)
Review
In aging, olfactory deficits have been associated with lower cognition and motor function. Olfactory dysfunction is also one of the earliest features of neurodegenerative disease. A comprehensive review of the neural correlates of olfactive function may reveal mechanisms underlying the associations among olfaction, cognition, motor function, and neurodegenerative diseases. Here, we summarize existing knowledge on the relationship between brain structural and functional measures and olfaction in older adults without and with cognitive impairment, including Alzheimer's disease. We identified 33 eligible studies (30 MRI/DTI,3 fMRI); 31 were cross-sectional, most assessed odor identification, and few examined multiple brain areas. Lower olfactory function was associated with smaller volumes in the temporal lobe (hippocampus,parahippocampal gyrus,fusiform gyrus), olfactory-related regions (piriform cortex,amygdala,entorhinal cortex), pre- and postcentral gyri, and globus pallidus. During aging, olfactory impairment may be associated with pathology in brain areas important for motor function and cognition, especially memory. Future longitudinal studies that include neuroimaging across different brain areas are warranted to determine the neurobiological changes underlying olfactory changes in the aging brain and the progression of neurodegeneration.
Topics: Humans; Aged; Neurodegenerative Diseases; Brain; Entorhinal Cortex; Hippocampus; Temporal Lobe; Magnetic Resonance Imaging; Cognitive Dysfunction
PubMed: 37913831
DOI: 10.1016/j.arr.2023.102095 -
ACS Chemical Neuroscience Jun 2023The functional and developmental unit of neurogenesis is neural stem cells (NSCs). These NSCs have self-renewal capacity and produce new neurons throughout life in... (Review)
Review
The functional and developmental unit of neurogenesis is neural stem cells (NSCs). These NSCs have self-renewal capacity and produce new neurons throughout life in different neurogenic niche. Neurogenesis in adult brain is associated with synaptic plasticity, learning, and memory in dentate gyrus (DG) of hippocampus and olfactory bulb. Remarkably, weakened neurogenesis has been viewed before the onset of different pathological hallmarks of neurological disorders. In this review, we have provided evidence which implicates impaired neurogenesis as a culprit in age associated neurological disorders with greater emphasis on Alzheimer's disease (AD). Moreover, an insight about the molecular and cellular regulation linked with altered neurogenesis in young and aging brain has also been discussed. This review further summarizes the therapeutic strategies for targeting the manipulation of the neural stem cell pool and factors affecting the pool involved in AD.
Topics: Adult; Humans; Alzheimer Disease; Hippocampus; Neural Stem Cells; Neurogenesis; Neurons
PubMed: 37261380
DOI: 10.1021/acschemneuro.3c00119