RESUMEN
Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.
Asunto(s)
Metilación de ADN , Neuronas , Humanos , Neuronas/metabolismo , Neuronas/fisiología , Femenino , Masculino , Adulto , Anciano , Adulto Joven , Envejecimiento/fisiología , Envejecimiento/genética , Caracteres Sexuales , Persona de Mediana Edad , Epigénesis Genética , Transcriptoma , Factores de Edad , Anciano de 80 o más Años , Lóbulo Frontal/metabolismo , Lóbulo Frontal/citología , Inactivación del Cromosoma X/genética , Corteza Cerebral/citología , Corteza Cerebral/metabolismoRESUMEN
A repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we investigate single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem motor and frontal cortices from C9-ALS, C9-FTD, and control donors. C9-ALS donors present pervasive alterations of gene expression with concordant changes in chromatin accessibility and histone modifications. The greatest alterations occur in upper and deep layer excitatory neurons, as well as in astrocytes. In neurons, the changes imply an increase in proteostasis, metabolism, and protein expression pathways, alongside a decrease in neuronal function. In astrocytes, the alterations suggest activation and structural remodeling. Conversely, C9-FTD donors have fewer high-quality neuronal nuclei in the frontal cortex and numerous gene expression changes in glial cells. These findings highlight a context-dependent molecular disruption in C9-ALS and C9-FTD, indicating unique effects across cell types, brain regions, and diseases.
Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Humanos , Demencia Frontotemporal/genética , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Transcriptoma/genética , Epigenoma , MutaciónRESUMEN
The mechanism of negative group delay (NGD) is used to understand the anticipatory capability of a retina. Experiments with retinas from bullfrogs are performed to compare with the predictions of the NGD model. In particular, whole field stochastic stimulations with various autocorrelation times are used to probe anticipatory responses from the retina. We find that the NGD model can reproduce essential features of experimental observations characterized by the cross correlations between the stimulation and the retinal responses. Experiments with dark light pulse stimulations further support the NGD mechanism, with the retina producing time-advanced pulse responses. However, no time-advanced pulse responses are produced by bright pulses. Counterintuitively, the NGD model shows that it is the delay in the system which gives rise to anticipation because of the negative feedback adaptation mechanism.