Abstract
The smooth transportation of substances through the brain extracellular space (ECS) is crucial to maintaining brain function; however, the way this occurs under simulated microgravity remains unclear. In this study, tracer-based magnetic resonance imaging (MRI) and DECS-mapping techniques were used to image the drainage of brain interstitial fluid (ISF) from the ECS of the hippocampus in a tail-suspended hindlimb-unloading rat model at day 3 (HU-3) and 7 (HU-7). The results indicated that drainage of the ISF was accelerated in the HU-3 group but slowed markedly in the HU-7 group. The tortuosity of the ECS decreased in the HU-3 group but increased in the HU-7 group, while the volume fraction of the ECS increased in both groups. The diffusion rate within the ECS increased in the HU-3 group and decreased in the HU-7 group. The alterations to ISF drainage and diffusion in the ECS were recoverable in the HU-3 group, but neither parameter was restored in the HU-7 group. Our findings suggest that early changes to the hippocampal ECS and ISF drainage under simulated microgravity can be detected by tracer-based MRI, providing a new perspective for studying microgravity-induced nano-scale structure abnormities and developing neuroprotective approaches involving the brain ECS.
Similar content being viewed by others
Referencess
Ahn, J.H., Cho, H., Kim, J.H., Kim, S.H., Ham, J.S., Park, I., Suh, S.H., Hong, S.P., Song, J.H., Hong, Y.K., et al. (2019). Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62–66.
Cavey, T., Pierre, N., Nay, K., Allain, C., Ropert, M., Loréal, O., and Derbré, F. (2017). Simulated microgravity decreases circulating iron in rats: role of inflammation-induced hepcidin upregulation. Exp Physiol 102, 291–298.
Chen, X., Liao, X., Dai, Z., Lin, Q., Wang, Z., Li, K., and He, Y. (2018). Topological analyses of functional connectomics: A crucial role of global signal removal, brain parcellation, and null models. Hum Brain Mapp 39, 4545–4564.
Colbourn, R., Naik, A., and Hrabetova, S. (2019). ECS dynamism and its influence on neuronal excitability and seizures. Neurochem Res 44, 1020–1036.
Da Mesquita, S., Fu, Z., and Kipnis, J. (2018). The meningeal lymphatic system: a new player in neurophysiology. Neuron 100, 375–388.
Fenstermacher, J., and Kaye, T. (1988). Drug “diffusion” within the brain. Ann NY Acad Sci 531, 29–39.
Han, H., Shi, C., Fu, Y., Zuo, L., Lee, K., He, Q., and Han, H. (2014). A novel MRI tracer-based method for measuring water diffusion in the extracellular space of the rat brain. IEEE J Biomed Health Inform 18, 978–983.
Han H B. (2019). Discovery of a new division system in brain and the regionalized drainage route of brain interstitial fluid (in Chinese). J Peking Univ Health Sci 51, 397–401.
Han, M., Kwon, I., Ha, J., Kim, J., Cha, M.J., Kim, Y.D., Heo, J.H., and Nam, H.S. (2020). Collateral augmentation treatment with a combination of acetazolamide and head-down tilt in a rat ischemic stroke model. J Clin Neurosci 73, 252–258.
Kermorgant, M., Nasr, N., Czosnyka, M., Arvanitis, D.N., Hélissen, O., Senard, J.M., and Pavy-Le Traon, A. (2020). Impacts of microgravity analogs to spaceflight on cerebral autoregulation. Front Physiol 11, 12.
Kramer, L.A., Hasan, K.M., Sargsyan, A.E., Marshall-Goebel, K., Rittweger, J., Donoviel, D., Higashi, S., Mwangi, B., Gerlach, D.A., and Bershad, E.M. (2017). Quantitative MRI volumetry, diffusivity, cerebrovascular flow, and cranial hydrodynamics during head-down tilt and hypercapnia: the SPACECOT study. J Appl Physiol 122, 1155–1166.
Kramer, L.A., Hasan, K.M., Stenger, M.B., Sargsyan, A., Laurie, S.S., Otto, C., Ploutz-Snyder, R.J., Marshall-Goebel, K., Riascos, R.F., and Macias, B.R. (2020). Intracranial effects of microgravity: a prospective longitudinal MRI study. Radiology 295, 640–648.
Lee, A.G., Mader, T.H., Gibson, C.R., Tarver, W., Rabiei, P., Riascos, R.F., Galdamez, L.A., and Brunstetter, T. (2020). Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update. NPJ Microgravity 6, 7.
Lei, Y., Han, H., Yuan, F., Javeed, A., and Zhao, Y. (2017). The brain interstitial system: Anatomy, modeling, in vivo measurement, and applications. Prog Neurobiol 157, 230–246.
Li, K., Han, H., Zhu, K., Lee, K., Liu, B., Zhou, F., Fu, Y., and He, Q. (2013). Real-time magnetic resonance imaging visualization and quantitative assessment of diffusion in the cerebral extracellular space of C6 glioma-bearing rats. Neurosci Lett 543, 84–89.
Li, Y., Han, H., Shi, K., Cui, D., Yang, J., Alberts, I.L., Yuan, L., Zhao, G., Wang, R., Cai, X., et al. (2020). The mechanism of downregulated interstitial fluid drainage following neuronal excitation. Aging Dis 11, 1407–1422.
Louveau, A., Smirnov, I., Keyes, T.J., Eccles, J.D., Rouhani, S.J., Peske, J. D., Derecki, N.C., Castle, D., Mandell, J.W., Lee, K.S., et al. (2015). Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341.
Ma, Q., Ineichen, B.V., Detmar, M., and Proulx, S.T. (2017). Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun 8, 1434.
Martin Paez, Y., Mudie, L.I., and Subramanian, P.S. (2020). Spaceflight associated neuro-ocular syndrome (SANS): A systematic review and future directions. Eye Brain Volume 12, 105–117.
Pajevic, S. (2019). Exploring the dynamics of brain extracellular space. Biophys J 117, 1781–1782.
Pandiarajan, M., and Hargens, A.R. (2020). Ground-based analogs for human spaceflight. Front Physiol 11, 6.
Patel, T.K., Habimana-Griffin, L.M., Gao, X., Xu, B., Achilefu, S., Alitalo, K., McKee, C.A., Sheehan, P.W., Musiek, E.S., Xiong, C., et al. (2019). Dural lymphatics regulate clearance of extracellular tau from the CNS. Mol Neurodegener 14, 11.
Qu, L., Chen, H., Liu, X., Bi, L., Xiong, J., Mao, Z., and Li, Y. (2010). Protective effects of flavonoids against oxidative stress induced by simulated microgravity in SH-SY5Y cells. Neurochem Res 35, 1445–1454.
Rasmussen, M.K., Mestre, H., and Nedergaard, M. (2018). The glymphatic pathway in neurological disorders. Lancet Neurol 17, 1016–1024.
Rasmussen, J.C., Kwon, S., Pinal, A., Bareis, A., Velasquez, F.C., Janssen, C.F., Morrow, J.R., Fife, C.E., Karni, R.J., and Sevick-Muraca, E.M. (2020). Assessing lymphatic route of CSF outflow and peripheral lymphatic contractile activity during head-down tilt using near-infrared fluorescence imaging. Physiol Rep 8, 12.
Roberts, D.R., Albrecht, M.H., Collins, H.R., Asemani, D., Chatterjee, A. R., Spampinato, M.V., Zhu, X., Chimowitz, M.I., and Antonucci, M.U. (2017). Effects of spaceflight on astronaut brain structure as indicated on MRI. N Engl J Med 377, 1746–1753.
Saito, R., and Tominaga, T. (2017). Convection-enhanced delivery of therapeutics for malignant gliomas. Neurol Med Chir (Tokyo) 57, 8–16.
Schmidt, B., Klingelhöfer, J., Perkes, I., and Czosnyka, M. (2009). Cerebral autoregulatory response depends on the direction of change in perfusion pressure. J Neurotrauma 26, 651–656.
Shetty, A.K., and Zanirati, G. (2020). The interstitial system of the brain in health and disease. Aging Dis 11, 200–211.
Shi, C., Lei, Y., Han, H., Zuo, L., Yan, J., He, Q., Yuan, L., Liu, H., Xu, G., and Xu, W. (2015). Transportation in the interstitial space of the brain can be regulated by neuronal excitation. Sci Rep 5, 17673.
Stern, P. (2016). Tracking extracellular space in the brain. Science 354, 1547.2.
Su, Y.T., Cheng, Y.P., Zhang, X., Xie, X.P., Chang, Y.M., and Bao, J.X. (2020). Acid sphingomyelinase/ceramide mediates structural remodeling of cerebral artery and small mesenteric artery in simulated weightless rats. Life Sci 243, 117253.
Sun, X.Q., Xu, Z.P., Zhang, S., Cao, X.S., and Liu, T.S. (2009). Simulated weightlessness aggravates hypergravity-induced impairment of learning and memory and neuronal apoptosis in rats. Behav Brain Res 199, 197–202.
Teng, Z., Wang, A., Wang, P., Wang, R., Wang, W., and Han, H. (2018). The effect of aquaporin-4 knockout on interstitial fluid flow and the structure of the extracellular space in the deep brain. Aging Dis 9, 808.
Tønnesen, J., Inavalli, V.V.G.K., and Nägerl, U.V. (2018). Super-resolution imaging of the extracellular space in living brain tissue. Cell 172, 1108–1121.e15.
Tsuchiya, K. (2021). Switching from apoptosis to pyroptosis: gasderminelicited inflammation and antitumor immunity. Int J Mol Sci 22, 426.
Wang, H., Duan, J., Liao, Y., Wang, C., Li, H., and Liu, X. (2017). Objects mental rotation under 7 days simulated weightlessness condition: an ERP study. Front Hum Neurosci 11, 553.
Wang, L., Li, Z., Tan, C., Liu, S., Zhang, J., He, S., Zou, P., Liu, W., and Li, Y. (2018). Physiological effects of weightlessness: countermeasure system development for a long-term Chinese manned spaceflight. Front Med 13, 202–212.
Wang, A., Wang, R., Cui, D., Huang, X., Yuan, L., Liu, H., Fu, Y., Liang, L., Wang, W., He, Q., et al. (2019a). The drainage of interstitial fluid in the deep brain is controlled by the integrity of myelination. Aging Dis 10, 937.
Wang, W., He, Q., Hou, J., Chui, D., Gao, M., Wang, A., Han, H., and Liu, H. (2019b). Stimulation modeling on three-dimensional anisotropic diffusion of MRI tracer in the brain interstitial space. Front Neuroinform 13, 6.
Xing, C., Wang, X., Gao, Y., Zhang, J., Liu, Y., Guo, Y., Wang, C., Feng, Y., Lei, Y., Zhang, X., et al. (2020). Lower body negative pressure protects brain perfusion in aviation gravitational stress induced by push-pull manoeuvre. J Physiol 598, 3173–3186.
Xu, F., Hongbin Han, F., Yan, J., Chen, H., He, Q., Xu, W., Zhu, N., Zhang, H., Zhou, F., and Lee, K. (2011). Greatly improved neuroprotective efficiency of citicoline by stereotactic delivery in treatment of ischemic injury. Drug Deliv 18, 461–467.
Yue, X., Mei, Y., Zhang, Y., Tong, Z., Cui, D., Yang, J., Wang, A., Wang, R., Fei, X., Ai, L., et al. (2019). New insight into Alzheimer’s disease: light reverses Aβ-obstructed interstitial fluid flow and ameliorates memory decline in APP/PS1 mice. Alzheimers Dement 5, 671–684.
Zhang, L.F., Chen, J.E., Ding, Z.P., and Ma, J. (1993). Cardiovascular deconditioning effects of long-term simulated weightlessness in rats. Physiologist 36, S26–S27.
Zhang, L.F., and Hargens, A.R. (2018). Spaceflight-induced intracranial hypertension and visual impairment: pathophysiology and countermeasures. Physiol Rev 98, 59–87.
Zhang, Y., Sun, L., Liu, E., Wang, A., and Yan, J. (2019). The olfactory stimulation slows down the substance clearance in the extracellular space of the hippocampus in rat brain. Biochem Biophys Res Commun 515, 429–435.
Zhao, G., Han, H., Yang, J., Sun, M., Cui, D., Li, Y., Gao, Y., and Zou, J. (2020). Brain interstitial fluid drainage and extracellular space affected by inhalational isoflurane: in comparison with intravenous sedative dexmedetomidine and pentobarbital sodium. Sci China Life Sci 63, 1363–1379.
Acknowledgements
This work was supported by the National Science Fund for Distinguished Young Scholars (61625102) and the National Natural Science Foundation of China (61971011). We thank Prof. Lina Qu and Guohua Ji of China Astronaut Research and Training Center for helping with the animal models and experiments. We thank Prof. Zhiqian Tong of Capital Medical University for his editing help and comments.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Compliance and ethics The author(s) declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Gao, Y., Han, H., Du, J. et al. Early changes to the extracellular space in the hippocampus under simulated microgravity conditions. Sci. China Life Sci. 65, 604–617 (2022). https://doi.org/10.1007/s11427-021-1932-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-021-1932-3