The Role of PHOX2B‐derived astrocytes in chemosensory control of breathing and sleep homeostasis

Key points

The embryonic PHOX2B‐progenitor domain generates neuronal and glial cells which together are involved in chemosensory control of breathing and sleep homeostasis. Ablating PHOX2B‐derived astrocytes significantly contributes to secondary hypoxic respiratory depression as well as abnormalities in sleep homeostasis. PHOX2B‐derived astrocyte ablation results in axonal pathologies in the retrotrapezoid nucleus.

Abstract

We identify a population of ∼ 800 RTN astrocytes derived from PHOX2B‐positive, OLIG3‐negative progenitor cells, that interact with PHOX2B‐expressing RTN chemosensory neurons. PHOX2B‐derived astrocyte ablation during early life results in adult‐onset O₂ chemoreflex deficiency. These animals also display changes in sleep homeostasis, including fragmented sleep and disturbances in delta power after sleep deprivation, all without observable changes in anxiety or social behaviours. Ultrastructural evaluation of the RTN demonstrates that PHOX2B‐derived astrocyte ablation results in features characteristic of degenerative neuro‐axonal dystrophy, including abnormally dilated axon terminals and increased amounts of synapses containing autophagic vacuoles/phagosomes. We conclude that PHOX2B‐derived astrocytes are necessary for maintaining a functional O₂ chemosensory reflex in the adult, modulate sleep homeostasis, and are key regulators of synaptic integrity in the RTN region, which is necessary for the chemosensory control of breathing. These data also highlight how defects in embryonic development may manifest as neurodegenerative pathology in an adult.

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