Journal Article

A novel chronic dural port platform for continuous collection of cerebrospinal fluid and intrathecal drug delivery in free-moving mice

Ito, Yuki, Rakugi, Hiromi, Morishita, Ryuichi, Sugimoto, Ken, Takeya, Yasushi, Shimizu, Hideo, Takami, Yoichi, Takeda, Shuko, Shimamura, Munehisa, Nakajima, Tsuneo, Oyama, Akane, Yamamoto, Koichi

2022

Overview

Background Cerebrospinal fluid (CSF) provides a close representation of pathophysiological changes occurring in the central nervous system (CNS); therefore, it has been employed in pathogenesis research and biomarker development for CNS disorders. CSF obtained from valid mouse models relevant to CNS disorders can be an important resource for successful biomarker and drug development. However, the limited volume of CSF that can be collected from tiny intrathecal spaces and the technical difficulties involved in CSF sampling has been a bottleneck that has hindered the detailed analysis of CSF in mouse models. Methods We developed a novel chronic dural port (CDP) method without cannulation for CSF collection of mice. This method enables easy and repeated access to the intrathecal space in a free-moving, unanesthetized mouse, thereby enabling continuous long-term CSF collection with minimal tissue damage and providing a large volume of high-quality CSF from a single mouse. When combined with chemical biosensors, the CDP method allows for real-time monitoring of the dynamic changes in neurochemicals in the CSF at a one-second temporal resolution in free-moving mice. Moreover, the CDP can serve as a direct access point for the intrathecal injection of CSF tracers and drugs. Results We established a CDP implantation and continuous CSF collection protocol. The CSF collected using CDP was not contaminated with blood and maintained physiological concentrations of basic electrolytes and proteins. The CDP method did not affect mouse’s physiological behavior or induce tissue damage, thereby enabling a stable CSF collection for up to four weeks. The spatio-temporal distribution of CSF tracers delivered using CDP revealed that CSF metabolism in different brain areas is dynamic. The direct intrathecal delivery of centrally acting drugs using CDP enabled real-time behavioral assessments in free-moving mice. Conclusions The CDP method enables the collection of a large volume of high-quality CSF and direct intrathecal drug administration with real-time behavioral assessment in free-moving mice. Combined with animal models relevant to CNS disorders, this method provides a unique and valuable platform for biomarker and therapeutic drug research.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animal behavior / Animal models / Animals / Biomarker / Biomarkers / Biomarkers - cerebrospinal fluid / Biomedical and Life Sciences / Biomedicine / Biosensors / Brain research / Cannulation / Central nervous system / Central Nervous System Diseases - cerebrospinal fluid / Central nervous system disorder / Cerebrospinal fluid / Dental cement / Disease Models, Animal / Drug delivery / Drug Delivery Systems / Drug development / Drugs / Hematology / Injections, Spinal / Intrathecal space / Laboratory animals / Medical research / Medicine, Experimental / Mice / Mouse model / Nervous system diseases / Neurobiology / Neurosciences / Pharmaceutical Preparations / Physiological aspects / Physiology / Proteins / Real-time monitoring / Spatial distribution / Temporal distribution / Tracers / Vehicles