A novel platform for a large-volume csf collection in the free-behaving mice as a preclinical model for biomarker development.

Objectives: With the emergence of disease-modifying therapies for dementia including Alzheimers disease and vascular dementia, there is an urgent need for the development of better biomarkers detecting early stage of dementia and predicting rate of progression. Cerebrospinal fluid (CSF) provides close representation of pathophysiological changes occurring in the central nervous system, and CSF biomarkers have proven to be useful for the diagnosis and prognosis of dementia. Preclinical work using mouse models would be useful to explore novel CSF biomarkers; however, detailed characterization of CSF has been challenging due to the difficulty in collecting large amount of CSF from mice. Here, we developed a novel technique that allows consistent recovery of CSF in the awake, free-moving mouse. Methods: Three-month-old C57/B6 male mice were used in this study. A small incision was made on the dura mater over the cisterna magna and a collecting tube was placed and fixed on the surface of the dura mater that CSF can be drawn via the small hole. Roller pump was connected to the tubing and CSF was continually collected in awake mobile mice. Results: We were able to collect a large volume of CSF from an awake mouse over a few days. Brain tissue had no apparent damage after the long-term collection and no detectable level of blood contamination was found in the collected CSF. This technique allowed a serial measurement of CSF biomarkers in a high-temporal resolution and a continuous administration of compounds / drugs into the subarachnoid space of awake mice. Conclusions: This technique would provide the opportunity to identify novel CSF biomarkers using mouse models of dementia.