To better identify and understand the gene regulatory pathways tied to neurological disease, researchers used Cre-Specific Nuclear Anchored Independent Labeling (cSNAIL), an enhanced, virus-based approach to isolate cells’ nuclei, to perform assessments in mice. The researchers found “GPe PV+ neuron-specific gene expression changes that suggested increased Hypoxia-inducible factor 2 alpha (Hif2a) signaling.” The findings were reported in The Journal of Neuroscience.

Using cSNAIL, researchers assessed the cell type-specific transcriptomic and epigenetic effects of dopamine depletion on PV+ and PV- cells within three brain regions of male and female mice: GPe, striatum, and cortex. The researchers also used INTACT system with modifications.

The heterozygous and transgenic mice were injected with adeno-associated viruses (AAV) and underwent dopamine depletion surgery.

After staining, imaging and dissecting, nuclei were extracted from tissue and genetic analysis began.


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The researchers identified “a transcriptional regulatory network mediated by the neuroprotective factor Hif2a as underlying neural circuit differences in response to dopamine depletion.”

GPe PV+ neurons were the only cell population with notable gene expression changes after dopamine depletion out of 6 cell populations.

“The evidence strongly supports an increase in HIF transcription factor activity in GPe PV+ neurons upon dopamine depletion,” the authors stated. “In the future, cSNAIL could be paired with protein assays to determine the precise [hypoxia-inducible factor] (HIF) protein expression levels, cellular localizations, and DNA binding events in GPe PV+ neurons in dopamine depletion.”

Reference

Lawler AJ, Brown AR, Bouchard RS, et al. Cell type-specific oxidative stress genomic signatures in the globus pallidus of dopamine depleted mice. J Neurosci. 2020 Nov 10:JN-RM-1634-20. doi:10.1523/JNEUROSCI.1634-20.2020