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Single-cell RNA-Seq reveals a developmental atlas of human prefrontal cortex

ABSTRACT: Mammalian prefrontal cortex contains billions of cells, some of which are known as neurons to play critical roles in memory, cognitive ability, decision making, social behavior etc. through participating into complex neural circuits. Although neural circuits build up in the late stage of human embryo development and even after birth, the diverse and functional cells start to generate and migrate to the appropriate location play essential roles as basis for developing future circuits. However, it remains challenging to identify cell types of developing human PFC and distinguish their developmental features. Here, to address these challenges, single cells from human embryos PFC were carried out for RNA-seq. Detailed analysis of neural progenitor cells (NPCs) illustrated a developmental feature of intermediate progenitor (IP) cells and revealed new marker genes of IP cells. We also mapped the neurogenesis timeline of PFC excitatory neurons and intrinsic singles regulating neuron maturation and circuit formation. Our screening and characterization approach provides a blueprint of human PFC development in early and mid embryonic stages, with which to systematically discover the cellular basis and molecular regulation of PFC function in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104276 | GEO | 2018/02/10

REPOSITORIES: GEO

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Project description:Background: Examining transcriptional regulation by existing antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Further, given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine (14 daily injections), and a rapidly acting, experimental, non-monoamine-based antidepressant, ketamine (single injection), in mice subjected to chronic social defeat stress, a validated model of depression, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results: We identified approximately equal numbers of responder and non-responder mice following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus than other brain regions; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in ketamine and imipramine responders were most similar in PFC, where the least transcriptional regulation occurred for each drug. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptible associated transcriptional changes as well as induced resilient associated transcription in PFC, with effects varying by drug and brain region studied. Conclusions: We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility and inducing resilience associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine. mRNA profiles of susceptibility to chronic social defeat stress as well as treatment response were generated across 4 separate brain regions, with a sample size of 3-5 per group.

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Single-cell RNA-Seq reveals a developmental atlas of human prefrontal cortex

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