Project 2 - Periarterial CSF Pumping: Dependence on State of Brain Activity
Our goal is to establish whether neural activity drives periarterial CSF pumping and thereby glymphatic clearance of metabolic waste. We postulate that periarterial CSF influx, which is prominent during NREM sleep and almost absent during wakefulness, primarily is driven by high-amplitude, coordinated oscillatory increases in neural activity during NREM sleep. We are basing the periarterial CSF pumping model on the well-documented mechanism of functional hyperemia, i.e., transient increases in blood flow and volume in response to neural activity. We postulate that CSF in parallel is pumped along the periarterial spaces to compensate for local or global changes in vascular volume. In this model, glymphatic fluid transport peaks during NREM sleep because coordinated neural activity drives larger amplitude changes in blood volume than in the awake space. Additional, permissive physiological changes, including a widening of the extracellular space, a decrease in heart and respiratory frequencies, and alterations in arterial wall pulsatility induced by vasodilation, support efficient glymphatic fluid transport in the dense neuropil during sleep.
Research Aims
Aim 1: Establishing the concept of periarterial CSF pumping and defining its cellular basis
Aim 2: Do brain states scale the amplitude of functional hyperemia and periarterial pumping?
Aim 3: Does arterial CSF influx predict glymphatic clearance in all brain states?
Publications
Ge GR, Song W, Giannetto MJ, Rolland JP, Nedergaard M, Parker KJ. Mouse brain elastography changes with sleep/wake cycles, aging, and Alzheimer's disease. Neuroimage. 2024 Jul 15;295:120662. doi: 10.1016/j.neuroimage.2024.120662. Epub 2024 May 31. PubMed PMID: 38823503; PubMed Central PMCID: PMC11409907
Delle C, Wang X, Nedergaard M. The Ocular Glymphatic System-Current Understanding and Future Perspectives. Int J Mol Sci. 2024 May 24;25(11). doi: 10.3390/ijms25115734. Review. PubMed PMID: 38891923; PubMed Central PMCID: PMC11172116.
Ding F, Sun Q, Long C, Rasmussen RN, Peng S, Xu Q, Kang N, Song W, Weikop P, Goldman SA, Nedergaard M. Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration. Brain. 2024 May 3;147(5):1726-1739. doi: 10.1093/brain/awae075. PubMed PMID: 38462589; PubMed Central PMCID: PMC11068329.
Gan Y, Thomas JH, Kelley DH. Gaps in the wall of a perivascular space act as valves to produce a directed flow of cerebrospinal fluid: a hoop-stress model. J R Soc Interface. 2024 Apr;21(213):20230659. doi: 10.1098/rsif.2023.0659. Epub 2024 Apr 3. PubMed PMID: 38565158; PubMed Central PMCID: PMC10987236.
Beinlich FRM, Asiminas A, Untiet V, Bojarowska Z, Plá V, Sigurdsson B, Timmel V, Gehrig L, Graber MH, Hirase H, Nedergaard M. Oxygen imaging of hypoxic pockets in the mouse cerebral cortex. Science. 2024 Mar 29;383(6690):1471-1478. doi: 10.1126/science.adn1011. Epub 2024 Mar 28. PubMed PMID: 38547288; PubMed Central PMCID: PMC11251491.
Delle C, Wang X, Giannetto M, Newbold E, Peng W, Gomolka RS, Ladrón-de-Guevara A, Cankar N, Schiøler Nielsen E, Kjaerby C, Weikop P, Mori Y, Nedergaard M. Transient but not chronic hyperglycemia accelerates ocular glymphatic transport. Fluids Barriers CNS. 2024 Mar 12;21(1):26. doi: 10.1186/s12987-024-00524-w. PubMed PMID: 38475818; PubMed Central PMCID: PMC10935920.
Raicevic N, Forer JM, Ladrón-de-Guevara A, Du T, Nedergaard M, Kelley DH, Boster K. Sizes and Shapes of Perivascular Spaces Surrounding Murine Pial Arteries. Research square. 2023 February 17. PubMed PMID: 36824982; PubMed Central PMCID: PMC9949243; DOI: 10.21203/rs.3.rs-2587250/v1.
Holstein-Rønsbo S, Gan Y, Giannetto MJ, Rasmussen MK, Sigurdsson B, Beinlich FRM, Rose L, Untiet V, Hablitz LM, Kelley DH, Nedergaard M. Glymphatic influx and clearance are accelerated by neurovascular coupling. Nature neuroscience. 2023 June;26(6):1042-1053. PubMed PMID: 37264158; PubMed Central PMCID: PMC10500159; DOI: 10.1038/s41593-023-01327-2.
Boster KAS, Cai S, Ladrón-de-Guevara A, Sun J, Zheng X, Du T, Thomas JH, Nedergaard M, Karniadakis GE, Kelley DH. Artificial intelligence velocimetry reveals in vivo flow rates, pressure gradients, and shear stresses in murine perivascular flows. Proceedings of the National Academy of Sciences of the United States of America. 2023 April 4;120(14):e2217744120. PubMed PMID: 36989300; PubMed Central PMCID: PMC10083563; DOI: 10.1073/pnas.2217744120.
Liu G, Ladrón-de-Guevara A, Izhiman Y, Nedergaard M, Du T. Measurements of cerebrospinal fluid production: a review of the limitations and advantages of current methodologies. Fluids and barriers of the CNS. 2022 December 15;19(1):101. PubMed PMID: 36522656; PubMed Central PMCID: PMC9753305; DOI: 10.1186/s12987-022-00382-4.
Delle C, Cankar N, Digebjerg Holgersson C, Hvorup Knudsen H, Schiøler Nielsen E, Kjaerby C, Mori Y, Nedergaard M, Weikop P. Long-term high-fat diet increases glymphatic activity in the hypothalamus in mice. Scientific reports. 2023 March 13;13(1):4137. PubMed PMID: 36914703; PubMed Central PMCID: PMC10011420; DOI: 10.1038/s41598-023-30630-y.
Gan Y, Holstein-Rønsbo S, Nedergaard M, Boster KAS, Thomas JH, Kelley DH. Perivascular pumping of cerebrospinal fluid in the brain with a valve mechanism. Journal of the Royal Society, Interface. 2023 September;20(206):20230288. PubMed PMID: 37727070; PubMed Central PMCID: PMC10509587; DOI: 10.1098/rsif.2023.0288.