ORCID

https://orcid.org/0000-0001-9434-6827

Date of Award

12-19-2024

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Lymphatic drainage from the central nervous system (CNS) has been noted and described for several hundred years, yet its physiological roles have remained unclear. The fluid homeostasis of the CNS has long stood as an area of scientific interest due to primary disorders including hydrocephalus. However, the early days of neuroimmunology leaned on the lack of lymphatic vasculature in the CNS as a contributing explanation for ‘immune privilege’ in the CNS. As a result, the importance of lymphatics in CNS homeostasis has remained poorly understood and controversial. Following a renaissance in interest in the contribution of lymphatics to CNS homeostasis, a series of works from many different labs has highlighted a role for lymphatics in numerous different CNS pathologies. Manipulation of lymphatic drainage from the CNS has been found to have effects on disease course and severity in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD); acute brain and spinal injury; and autoimmune diseases including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). These studies have revealed a role of lymphatics in the etiology and progression of disease and thus a potential target of therapeutic intervention. However, the implication of lymphatics in diseases of the CNS has outpaced our fundamental understanding of the core physiology of the CNS lymphatic system. Unfortunately, the scientific understanding and interventional toolbox of general lymphatic function and dysfunction are also relatively naïve, so targeting lymphatics has not been a simple matter of repurposing treatments from other, primary lymphatic pathologies. As a result, progress in developing therapeutic approaches targeting the CNS lymphatic system has been extremely limited despite increasing knowledge of its involvement in disease. Therefore, we set out to expand our understanding of the basic CNS-specific physiology of lymphatic drainage to define areas of specific deficit and therapeutic potential. We characterized the forces acting on cerebrospinal fluid (CSF) outflow into lymph through both the deep and superficial cervical lymphatic network (dcLN and scLN respectively) in collecting lymphatic vessels (cLVs) afferent to the nodes. We found that dcLN outflow was driven by extrinsic forces, but collecting vessels exhibit active tonic behavior. scLN uptake of CSF occurred through the nasal compartment. scLN cLVs exhibited active pumping, but CSF outflow into the nasal compartment was passive and decoupled from scLN drainage. To better understand the interplay of these two systems, we investigated postural challenge and ligation of either or both sets of cLVs. We found that dcLN outflow was essentially constant, while acute postural increases in intracranial pressure (ICP) robustly recruited nasal-scLN outflow. dcLN-afferent cLV ligation also recruited the scLN outflow pathway. While ligation did not result in changes in resting ICP, we measured increased outflow resistance in the dcLN- and dual-ligation conditions, suggesting diminished fluid throughput in the CNS. Taken together, our results highlight the distinct physiological roles of the deep and superficial cervical lymphatic networks in CNS homeostasis. These insights identify novel therapeutic targets and lay the groundwork for metrics and mechanisms in future studies with experimental models of disease.

Language

English (en)

Chair and Committee

Jonathan Kipnis

Committee Members

Claudia Han; David Holtzman; Gwendalyn Randolph; Helene Benveniste; Jennifer Strahle; Sarah Ackerman

Available for download on Tuesday, January 13, 2026

Included in

Neurosciences Commons

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