Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution

Area of Science:

• Neuroscience
• Endocrinology
• Chronobiology

Background:

• The choroid plexus (ChP) acts as a brain barrier, regulating cerebrospinal fluid (CSF) composition to modulate brain states.
• Understanding diurnal variations in ChP and CSF is crucial for comprehending daily brain function.
• The transthyretin (TTR) protein, a thyroid hormone chaperone, is secreted by the ChP.

Purpose of the Study:

• To develop and utilize an integrated platform for analyzing diurnal variations in male mouse ChP and CSF.
• To investigate the molecular mechanisms underlying diurnal regulation of ChP and CSF.
• To explore the role of TTR in diurnal brain state modulation.

Main Methods:

• Ribosome profiling of ChP epithelial cells to identify diurnal translatome differences.
• ChP and CSF metabolomics and blood-CSF barrier analyses.
• Real-time tracking of CSF-TTR using Ttr^mNeonGreen mice and fiber photometry.

Main Results:

• Diurnal translatome differences were observed in ChP epithelial cells, including metabolic, secreted, and barrier components.
• Metabolomic and barrier analyses revealed diurnal changes in metabolites and cellular junctions in ChP and CSF.
• Diurnal TTR variation in the ChP was dependent on the Bmal1 clock gene, and CSF TTR levels correlated with CSF thyroid hormone levels.

Conclusions:

• The study presents an integrated platform for investigating diurnal control of brain states by the ChP and CSF.
• Diurnal rhythms in ChP and CSF composition, particularly TTR, play a role in regulating thyroid hormone levels.
• These findings provide insights into the chronobiology of brain function and CSF regulation.