Advances in transcriptomics give single cell views of brain development and disease

New approaches highlight cellular processes associated with addiction, degeneration and normal development

Advances in high-throughput RNA sequencing technologies are opening windows into how normal and pathological brain processes develop at the single cell level. The findings were presented at Neuroscience 2019, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.

RNA transcripts produced in a cell can highlight the cellular processes and mechanisms at work in specific circumstances or in a specific cell type. As technological improvements make the study of a cell’s complete set of RNA transcripts — its transcriptome — more achievable, scientists are beginning to apply transcriptomics to the study of the central nervous system to gain a better understanding of genetic and epigenetic changes that underlie brain development and disease.

Today’s new findings show that:

  • In a mouse model of cocaine addiction, repeated drug exposure may “scar” gene regulation machinery, permanently altering how neurons function in the nucleus accumbens, part of the brain’s reward center (Philipp Mews, University of Pennsylvania).
  • Single cell RNA profiling identifies the genes and processes that guide the development of specific cell types in the human cerebral cortex from prenatal development to 50 years of age (Arnold Kriegstein, University of California, San Francisco).
  • Big data analysis of single cell transcriptional profiles reveals biological changes that are unique to Alzheimer’s disease and do not occur during the normal human aging process (Vivek Swarup, University of California, Irvine).

“The neuroscience research presented today shows that advances in transcriptomics technology overcome basic challenges in neuroscience by letting us look inside the molecular machinery of brain cells, one cell at a time,” said press conference moderator Naomi Habib, PhD, an assistant professor at Edmond & Lily Safra Center for Brain Sciences (ELSC) who studies cognitive decline and resilience is a pioneer in single cell transcriptomics. “These advances give us a better understanding of the process of normal development as well as more insight into pathological states, such as drug addiction and neurodegenerative disease.”

This research was supported by national funding agencies including the National Institutes of Health and private funding organizations. Find out more about transcriptomics on BrainFacts.org.

Related Neuroscience 2019 Presentation

Minisymposium: Novel Mechanisms of Neuronal Alternative Splicing and Strategies to Correct Aberrant-Splicing

Tuesday, Oct. 22, 8:30 – 11:00 a.m., Room S102

Transcriptomics Press Conference Summary

  • Overall, these studies show that transcriptomics, the study of the full complement of RNA molecules produced in a cell or group of cells, has become a useful tool for probing the molecular changes within brain cells during normal development or during diseases such as drug addiction and Alzheimer’s disease.

Epigenetic Priming Underlies Transcriptional Disruption Linked to Cocaine Relapse

Philipp Mews, philipp.mews@gmail.com, Abstract 453.07

  • Drugs of abuse hijack brain reward pathways and switch “on” or “off” numerous genes in neurons in the nucleus accumbens, a key region in the brain’s reward center.
  • These changes in gene activity can drive lasting changes in neuronal connectivity that may ultimately lead to maladaptive behaviors such as craving and relapse.
  • In a mouse model of cocaine addiction, repeated exposure to the drug creates lasting “scars” in DNA-protein complexes that changes how easily certain genes can be transcribed, priming neurons for rapid activation by future drug exposure and establishing a potential mechanism for relapse.
  • Future work will identify the precise mechanisms that establish and preserve the molecular changes in distinct types of reward neurons and determine if these drug-induced changes are reversible.

Single Cell Transcriptomic Analysis of Human Cortical Development Throughout the Prenatal and Postnatal Life

Arnold Kriegstein, Arnold.Kriegstein@ucsf.edu, Abstract 010.04

  • The application of single-nucleus RNA sequencing to postmortem tissue samples was used to profile gene expression patterns in specific cell types in human cerebral cortex from prenatal development to 50 years of age.
  • Analyses identified genes and pathways that underlie processes of human brain development, such as neuronal specification, synapse formation, gliogenesis, and myelination.
  • The first single cell atlas of prenatal and postnatal human cortical development could be used to investigate processes and cell types involved in neurodevelopmental disorders and aid in the development of targeted therapies.

Single Cell Transcriptome Identifies Conserved Transcriptomic Alterations in Alzheimer’s Disease

Vivek Swarup, vswarup@uci.edu, Abstract 014.03

  • Researchers used single cell RNA sequencing to profile the transcriptomes of thousands of postmortem brain cells from individuals with and without Alzheimer’s disease.
  • Big data analysis identified fundamental biological processes that are altered in Alzheimer’s disease but unaffected in the normal human aging process, which could lead to the development of effective therapeutics that target genes and pathways specific to Alzheimer’s disease and distinct from healthy aging.
  • Certain networks of genes change together in the progression of Alzheimer’s disease, implying that regulatory genes such as transcription factors could serve as useful therapeutic targets.

Source – Society for Neuroscience

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