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

Ryann M Fame; Peter N Kalugin; Boryana Petrova; Huixin Xu; Paul A Soden; Frederick B Shipley; Neil Dani; Bradford Grant; Aja Pragana; Joshua P Head; Suhasini Gupta; Morgan L Shannon; Fortunate F Chifamba; Hannah Hawks-Mayer; Amanda Vernon; Fan Gao; Yong Zhang; Michael J Holtzman; Myriam Heiman; Mark L Andermann; Naama Kanarek; Jonathan O Lipton; Maria K Lehtinen

doi:10.1038/s41467-023-39326-3

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

Nat Commun. 2023 Jun 22;14(1):3720. doi: 10.1038/s41467-023-39326-3.

Authors

Ryann M Fame^{1

2}, Peter N Kalugin^{1

3

4}, Boryana Petrova¹, Huixin Xu¹, Paul A Soden¹, Frederick B Shipley^{1

5}, Neil Dani¹, Bradford Grant¹, Aja Pragana¹, Joshua P Head¹, Suhasini Gupta¹, Morgan L Shannon¹, Fortunate F Chifamba^{6

7}, Hannah Hawks-Mayer^{6

7}, Amanda Vernon^{8

9

10}, Fan Gao^{8

9

10

11}, Yong Zhang¹², Michael J Holtzman¹², Myriam Heiman^{8

9

10}, Mark L Andermann^{3

5

13}, Naama Kanarek^{1

10}, Jonathan O Lipton^{6

7}, Maria K Lehtinen^{14

15

16

17}

Affiliations

¹ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
² Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA.
³ Graduate Program in Neuroscience, Harvard Medical School, Boston, MA, 02115, USA.
⁴ Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA, 02115, USA.
⁵ Graduate Program in Biophysics, Harvard University, Cambridge, MA, 02138, USA.
⁶ Department of Neurology and the F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
⁷ Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02115, USA.
⁸ Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA.
⁹ Picower Institute for Learning and Memory, Cambridge, MA, USA.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Lyterian Therapeutics, South San Francisco, 94080, CA, USA.
¹² Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO, 63110, USA.
¹³ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
¹⁴ Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA. maria.lehtinen@childrens.harvard.edu.
¹⁵ Graduate Program in Neuroscience, Harvard Medical School, Boston, MA, 02115, USA. maria.lehtinen@childrens.harvard.edu.
¹⁶ Graduate Program in Biophysics, Harvard University, Cambridge, MA, 02138, USA. maria.lehtinen@childrens.harvard.edu.
¹⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA. maria.lehtinen@childrens.harvard.edu.

Abstract

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Ttr^mNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Biological Transport
Blood-Brain Barrier* / metabolism
Brain / metabolism
Choroid Plexus* / metabolism
Male
Mice
Prealbumin / genetics
Prealbumin / metabolism
Thyroid Hormones / metabolism

Substances

Thyroid Hormones
Prealbumin

Abstract

Publication types

MeSH terms

Substances

Grants and funding